tbuckley/cabot-search huggingface dataset:
Endoscopic ultrasonography in a children's hospital: succesful applications of adult techniques to typical paediatric pathologies
Authors: A Pane, P De Angelis, F Torroni, T Caldaro, G Federici, L Dall'Oglio
Journal: Endoscopy (2006)

B. Endoscopic ultrasonography (EUS) has been worldwide and fully applied to adulthood pathologies such as cancer and pancreatic pseudocysts. There is no similar experience in paediatrics, either because of reduced availability of dedicated linear scopes, or because childhood diseases are still approached by traditional techniques in most centres.
Measuring the Value of Prescription Drugs
Authors: Peter J. Neumann, Joshua T. Cohen
Journal: New England Journal of Medicine (2015)

Interview with Dr. Peter Neumann on the use of various new value-based frameworks for assessing drugs and drug prices. (08:22)Download Escalating drug prices have spawned a flurry of initiatives designed to help physicians, payers, and patients understand the value of new therapies and make better choices about their use. But these efforts have revealed numerous analytic and implementation challenges.
Abstract LB-206: Target validation of C4.4a (LYPD3) as a target for antibody-drug conjugates for the treatment of squamous cell carcinoma of different origin.
Authors: Gabriele Leder, Yong-Jiang Cao, Lars Linden, Sven Golfier, Oliver von Ahsen, Claudia Schneider, Joerg Willuda, Kirk McLean, Hans-Dieter Pohlenz, Bertolt Kreft, Karl Ziegelbauer
Journal: Cancer Research (2013)

Abstract C4.4a (LYPD3) is a GPI-anchored cell surface protein with unknown physiological function, although it has been speculated that it might play a role in tumor invasion and metastasis formation. In addition, over-expression of C4.4a correlates with a malignant phenotype and poor prognosis in several cancer indications. As a result of comprehensive gene expression profiling, we report that the C4.4a transcript is being significantly up-regulated in human non-small cell lung cancer (NSCLC) as well as in other tumors compared to the respective normal tissue. This finding was confirmed in IHC studies showing strong C4.4a protein expression on the surface of tumor cells particularly in lung squamous cell carcinoma. Interestingly, a high incidence of C4.4a protein expression was found in a number of additional cancers such as stomach, bladder, colorectal, ovarian, prostate, hepatocellular as well as SCC of the head and neck. In marked contrast to tumors, C4.4a expression in normal tissues is restricted to esophagus, cervix and the outer epithelial layer of skin (stratum spinosum and stratum granulosum). Employing FACS and IHC analyses, several model systems were identified expressing C4.4a in vitro and in vivo. Subsequently, Mab-Zap assays were used to demonstrate efficient internalization of C4.4a in endogenously expressing cells as well as in cells transfected to over-express C4.4a. In summary, the observed strong over-expression of C4.4a in tumors, its very limited expression in normal tissue as well as its ability to rapidly internalize make it a promising target for the generation of antibody-drug conjugates for the treatment of several cancer indications, in particular lung squamous cell carcinoma. Citation Format: Gabriele Leder, Yong-Jiang Cao, Lars Linden, Sven Golfier, Oliver von Ahsen, Claudia Schneider, Joerg Willuda, Kirk McLean, Hans-Dieter Pohlenz, Bertolt Kreft, Karl Ziegelbauer. Target validation of C4.4a (LYPD3) as a target for antibody-drug conjugates for the treatment of squamous cell carcinoma of different origin. [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 LB-206. doi:10.1158/1538-7445.AM2013-LB-206
TM-03 * THE HSP90 INHIBITOR GANETESPIB IS AN EFFECTIVE THERAPY FOR GLIOBLASTOMA THAT BLOCKS EGFR-DRIVEN TUMOR GROWTH
Authors: J. Driscoll, N. Vad, S. Jagannathan
Journal: Neuro-Oncology (2014)

Malignant gliomas are highly aggressive primary brain tumors with few treatment options and invariably fatal outcomes. The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is hyperactivated through gene amplification or mutation in many cancers. EGFR activity is associated with increased cell proliferation, disease progression and therapeutic resistance. Intratumoral heterogeneity of EGFR arises as a signature pathogenetic events in the highly aggressive and invariably fatal brain tumor glioblastoma multiforme (GBM). Functional blockade of the EGFR kinase activity alone does not achieve maximal therapeutic benefit to support the role for EGFR kinase-independent functions. We performed a high-throughput, pharmacologic screening to identify EGFR-targeted therapeutics in glioma cells engineered to overexpress either a high or low copy number of EGFR wildtype (WT), a constitutively active mutant EGFR-vIII or an EGFR kinase-dead (KD) mutant. We discovered that the heat shock protein (HSP)90 inhibitor ganetespib selectively and potently killed glioma cells that overexpressed either the WT, vIII or KD forms of EGFR (IC50 ∼20-40nM). Real-time measurements demonstrated that ganetespib reduced proliferation, induced caspase-dependent apoptosis and inhibited glioma migration. Overexpression of the EGFR-WT, vIII or KD forms significantly increased intracellular ATP levels and WT, vIII and KI EGFR all translocalized to the mitochondria. Ganetespib addition rapidly reduced ATP in cells that overexpressed either kinase-active or kinase-inactive forms. Ganetespib reduced the proliferation of human patient GBM patient-derived tumor stem cells and effectively impaired the growth of subcutaneously placed glioma implants in nude mouse models. Ganetespib impairs the EGFR kinase-(in)dependent activities with the potential benefit to overcome intratumoral heterogeneity benefit and improve GBM patient outcome.
AB0751 Semi-automatic quantitative investigation of wrist cartilage in humans using 3t mri
Authors: J. Zink, P. Souteyrand, S. Guis, C. Chagnaud, Y. Le Fur, D. Militianu, J. P. Mattei, M. Rozenbaum, I. Rosner, H. Boudinet, M. Bernard, D. Bendahan
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Because of its reduced thickness at the carpus level, the MRI identification of cartilage abnormalities has been initially discarded from the usual rheumatologic diagnostic scores and just recently introduced as a qualitative variable related to joint space narrowing. <h3>Objectives</h3> In the present study we aimed at determining whether carpal cartilage area can be measured using high-field MRI area through a semi-automatic method. We also compared the results related to two different MRI sequences. <h3>Methods</h3> The study was conducted in 14 healthy volunteers after they provided their written informed consent. MRI investigations were performed at 3T using two 3D sequences i.e. VIBE and DESS for the analysis of carpal cartilage. Cartilage surface was measured on a three-dimensional reconstruction using a conventional image processing radiology software. The protocol received the agreement from the local ethics committee. <h3>Results</h3> Cartilage measurements performed by two different operators and twice by the same operator showed a very good reproducibility regardless the MRI sequence used. A 15% interindividual variability for the cartilage area was quantified within this control group. Interestingly, the wrist cartilage area was linearly related to the carpal bone height and so for results obtained with both MRI sequences. <h3>Conclusions</h3> Using high-field MRI, we reported a very reproducible semi-automatic method of cartilage surface measurement in wrist. The measurements were performed on a MRI section accurately defined thanks to 3D acquisitions. The large variability of the corresponding measurements illustrated that cartilage area cannot be used as a stand-alone diagnostic criterion. The standardized linear relationship between wrist cartilage area and carpal bone height captures the natural diversity of these measurements and provides a promising index for future diagnostic and therapeutic studies in the field of rheumatologic diseases. <h3>Disclosure of Interest</h3> None Declared
Chronic Sialadenitis With Marked Lymphadenopathy Mimicking Lymphoma on FDG PET/CT
Authors: Yiyan Liu
Journal: Clinical Nuclear Medicine (2014)

A 53-year-old woman with bilateral proptosis and diffuse lymphadenopathy had FDG PET/CT for the evaluation of lymphoma. There were significant enlargements of the lacrimal glands, thickening of the intraorbital muscles, prominent parotid/submandibular glands, and FDG-avid lymphadenopathy in the neck, right axilla, and mediastinum. The findings were suggestive of either lymphoma or sarcoidosis. Subsequent biopsy of the left lacrimal gland revealed chronic inflammation with lymphoid aggregate formation, atrophy, and fibrosis consistent with chronic sialadenitis, and an incisional biopsy of the cervical lymph node showed salivary gland tissue with inflammation as well. There was no pathological evidence of lymphoma or sarcoidosis.
Abstract 3150: Characterizing the effects of somatic mutations in splice factors on the transcriptome.
Authors: Angela N. Brooks, Youzhong Wan, Peter Choi, Rui Jing, David S. DeLuca, Carrie Sougnez, Juliann Chmielecki, Marcin Imielinski, Gad Getz, Catherine J. Wu, Matthew Meyerson
Journal: Cancer Research (2013)

Abstract Recent studies have identified recurrent somatic mutations in splice factors, including SF3B1 and U2AF1, in myelodysplastic syndromes, chronic lymphocytic leukemias, breast cancer, and lung adenocarcinoma. In one study, 91 tumor and matched normal whole-exomes were sequenced from patients with CLL and the second most frequently mutated gene was SF3B1. Analysis of 187 whole-exomes in lung adenocarcinoma and matched normals revealed recurrent somatic mutations in the splice factor U2AF1 in 3% of cases. In addition to U2AF1 mutations, recurrent truncating mutations were observed in a putative splice factor, RBM10, in 4% of lung adenocarcinomas. The recurrence of somatic mutations in splice factors in multiple tumor types suggests that alterations in RNA splicing may play an important role in tumorigenesis. Although these mutations have been identified in cancer genomes, the effect on the cancer transcriptome has yet to be fully explored; therefore, we do not understand how mutations in splice factors can contribute to tumorigenesis. We hypothesize that somatic mutations in splice factors cause alterations in mRNA splicing of important cancer genes. We are using a computational tool called JuncBASE to identify alternative splicing in tumor transcriptomes from RNA-Seq data. We are then associating somatic mutations in splice factors, found from whole-exome sequencing, with splicing signatures identified through RNA-Seq. Preliminary results on the identification of splice events associated with SF3B1 mutations in CLL reveal novel isoforms of multiple genes specifically expressed in SF3B1 mutant samples. Additionally, we examined the effects of SF3B1, U2AF1, and RBM10 mutations on tumor transcriptomes using RNA-Seq data from The Cancer Genome Atlas. Citation Format: Angela N. Brooks, Youzhong Wan, Peter Choi, Rui Jing, David S. DeLuca, Carrie Sougnez, Juliann Chmielecki, Marcin Imielinski, Gad Getz, Catherine J. Wu, Matthew Meyerson. Characterizing the effects of somatic mutations in splice factors on the transcriptome. [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 3150. doi:10.1158/1538-7445.AM2013-3150
FREQUENCY AND PREDICTORS OF PACEMAKER IMPLANTATION AFTER CATHETER ABLATION OR CARDIOVERSION FOR ATRIAL FIBRILLATION
Authors: Peter Noseworthy, Abhishek Deshmukh, Haas Lindsey, Van Houten Holly, Schilz Sara, Nilay Shah, Suraj Kapa, Paul Friedman, Douglas Packer, Samuel Asirvatham
Journal: Journal of the American College of Cardiology (2015)
Genomics--from the lab to clinical practice
Authors: F. Godlee
Journal: BMJ (2013)

There are about 20 000 genes in the human genome. Until recently, clinicians seeking to diagnose a genetic condition have had to select single genes to be sequenced. The process is slow, expensive, and often unsuccessful. Now that the cost of DNA sequencing has fallen so dramatically, it’s cheaper and easier to sequence the entire genome, with huge potential benefit to our understanding of disease. 

But this bounty brings with it clinical and ethical questions, as Caroline Wright and colleagues explain (doi:10.1136/bmj.f6845). Who should be tested? How much of the genome should be sequenced? What should patients be told? What do we do about …
A8.23 E and Id proteins influence invariant Natural Killer T cell sublineage differentiation and proliferation
Authors: Martin H Stradner, Louise M D’Cruz, Cliff Y Yang, Ananda W. Goldrath
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Invariant Natural Killer T (iNKT) cells are able to produce large amounts of cytokines within hours of activation. Disease outcome is known to be influenced depending on the type of cytokines produced by iNKT cells. Recently, three functionally and transcriptionally defined subsets of iNKT cells have been described; TBET + NKT1 cells produce IFNg and IL-4, while PLZF + NKT2 cells produce IL-4 and IL-13, and NKT17 cells are positive for RORγt and produce IL-17. However, the factors governing the development of these unique iNKT sublineages during thymic development are unknown. Here we explored the mechanism by which E protein transcription factors and their negative regulators, the Id proteins control the development of iNKT sublineages after positive selection. <h3>Materials and Methods</h3> We generated Vα14-Jα18 transgenic (Vα14tg) mice conditionally deficient for the E proteins Tcf3 (E2A) and Tcf12 (HEB). Id2-YFP and Id3-GFP reporter mice were used to analyse expression of Id proteins. Functional relevance of these findings was confirmed in Id2 and Id3 knock-out mice. iNKT cells were analysed using flow cytometry, real-time PCR and chromatin immunoprecipitation. <h3>Results</h3> We found that E proteins directly bound the PLZF promoter and were required for expression of this lineage-defining transcription factor and for the maturation and expansion of thymic iNKT cells. Moreover, expression of the negative regulators of E proteins, Id2 and Id3, defined distinct iNKT cell sublineages. Id3 was expressed in PLZF<sup>high</sup> NKT2 cells and loss of Id3 allowed for increased thymic iNKT cell expansion and abundance of the PLZF<sup>+</sup> NKT2 sublineage. Id2 was expressed in TBET<sup>+</sup> NKT1 cells and both Id proteins were required for the formation of this sublineage. <h3>Conclusions</h3> We provide insight into E and Id protein regulation of iNKT cell proliferation and differentiation to specific sublineages during development in the thymus.
DNA Nanotechnology for Cancer Therapeutics
Authors: Vinit Kumar, Stefano Palazzolo, Samer Bayda, Giuseppe Corona, Giuseppe Toffoli, Flavio Rizzolio
Journal: Theranostics (2016)

DNA nanotechnology is an emerging and exciting field, and represents a forefront frontier for the biomedical field.The specificity of the interactions between complementary base pairs makes DNA an incredible building material for programmable and very versatile two-and three-dimensional nanostructures called DNA origami.Here, we analyze the DNA origami and DNA-based nanostructures as a drug delivery system.Besides their physical-chemical nature, we dissect the critical factors such as stability, loading capability, release and immunocompatibility, which mainly limit in vivo applications.Special attention was dedicated to highlighting the boundaries to be overcome to bring DNA nanostructures closer to the bedside of patients.
Abstract 2118: Particulate chromate induces persistent DNA double strand breaks resulting in disruption of homologous recombination repair in human lung cells
Authors: Qin Qin, Hong Xie, Amie L. Holmes, Sandy S. Wise, John P. Wise
Journal: Cancer Research (2012)

Abstract Hexavalent chromium (VI) is a well-documented respiratory toxicant and carcinogen. The most carcinogenic form is the particulates, which produce numerous types of DNA damage including DNA double strand breaks. The aim of this study is to determine the genotoxicity of particulate chromate and investigate cellular responses of repair proteins after chronic exposure. We used zinc chromate as a representative hexavalent chromium compound because it has been shown to be carcinogenic and induce tumors in epidemiology studies and experimental animals. We investigated the DNA double strand break formation using both comet assay and immunofluorescence staining. We exposed cells to zinc chromate for 24, 48, 72 96 and 120 hours and found it induced concentration-dependent increases in DNA double strand breaks by both measures. We further investigated the kinetics of repair protein after chronic zinc chromate exposure. We developed human lung cells expressing green fluorescent protein-tagged 53BP1 (GFP-53BP1) and generated time-lapse videos of chromate treated cells. We observed residual focal formation of 53BP1 after chronic zinc chromate exposure, which indicate some DNA double strand breaks persist. There are two repair pathways that can be utilized to repair DNA double strand breaks. Non-homologous end joining (NHEJ) is active throughout the cell cycle while homologous recombination (HR) is active in late S and G2 phases. We first investigated the sub-cellular distribution of HR proteins including MRE11, phophorylated ATM and Rad51. We found that the nuclear fraction of HR repair proteins increased in 24 hours indicating HR is active. However, it largely decreased over time. We also observed concentration- and time-dependent decrease in Rad51 foci formation, which strongly suggest that HR is inhibited. Future work will focus on elucidating NHEJ repair pathway and identifying key proteins involved in transitions between two repair pathways. This work was supported by NIEHS grant ES016893 (J.P.W.), cooperative agreement #EP-08-01 through the Maine Space Grant Consortium (J.P.W.) and the Maine Center for Toxicology and Environmental Health at the University of Southern Maine. 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 2118. doi:1538-7445.AM2012-2118
SP0166 New guidelines for the appropriate engagement of people with RMDS in clinical trials
Authors: M.H. Buch
Journal: Annals of the Rheumatic Diseases (2013)

Clinical research, and in particular, clinical trials represent the core focus of research activity with randomised controlled trials (RCT) the gold-standard method for evaluating intervention. Several factors contribute to the success or failure of a clinical trial including clinical applicability, obstacles to clinician and patient involvement, study design, analysis etc. People with RMD are motivated to participate in clinical studies for several reasons including the opportunity of receiving state of the art management, greater attention from health professionals and a strong sense of altruism. Nevertheless, poor recruitment is recognised as a major contributor to study failure. There are a variety of factors that may contribute to this, of which effective communication and publicising of clinical trials to people with RMD is a crucial factor. Adopting more pro-active approaches such as direct advertisement to patients may improve recruitment and bring the additional benefit of raising the profile of RMD research. Such an approach however may introduce distinct ethical issues and might also impact on the efficient delivery of the trial objectives. How best to engage people with RMD is an area that needs further attention and wider discussion. This lecture will discuss the issues around better engagement of people with RMD in clinical trials and discuss whether there is a need for guidelines to ensure a more broadly applicable standard for future trials. <h3>Disclosure of Interest</h3> None Declared
Abstract LB-289: Angiogenesis and lymphangiogenesis in mucoepidermoid carcinoma of the minor salivary glands
Authors: Frederico O. Gleber-Netto, Taynara Nunes Guedes Florencio, Silvia Ferreira Sousa, Elismauro Francisco Mendonça, Carolina Cavalieri Gomes, Maria Cassia Ferreira Aguiar
Journal: Cancer Research (2011)

Abstract The purpose of this study was to investigate angiogenesis and lymphangiogenesis in mucoepidermoid carcinoma (MEC) of the minor salivary glands as potential predictors of tumor behavior. Intratumoral and peritumoral neoformed (NMVD) and lymphatic microvessel density (LMVD) were evaluated by CD105 and D2–40 immunohistochemistry, respectively. D2–40, VEGF-A, and VEGF-C immunoexpression were also investigated in tumor parenchyma. Twenty-six paraffin-embedded MEC samples were included in the study. Palate (50%) and buccal mucosa (19.2%) were the main affected sites. Sixteen (61.5%) tumors were low-grade, 6 (23.1%) intermediate-grade, and 4 (15.4%) high-grade. Twenty (77%) cases were clinically T1-T2, and 6 (23%) were T3-T4. Nodal metastasis occurred in 3 (11.5%) cases and distant metastasis in 1 (3.8%). Three (11.5%) cases recurred, and 3 (11.5%) patients died from disease. NMVD mean was 19.58±13.91 (400x field) for intratumoral evaluation and 10.90±7.79 (400x field) for peritumoral evaluation. LMVD mean was 5.66±3.43 (400x field) for peritumoral evaluation and 0.54±3.43 (400x field) for intratumoral evaluation. Just 6 (23.1%) cases reveal intratumoral lymphatic vessels. Twenty-two (84,6%) cases showed D2–40 in neoplastic cells, mainly in epidermoid type. Fifteen (57.7%) cases were positive for VEGFA, and 11 (42.3%) were positive for VEGF-C. A positive association was observed between VEGF-A positivity and intratumoral NMVD (p=0.05). Cases with nodal metastasis, altogether, were related to low intratumoral NMVD, high peritumoral LMVD, D2–40 expression and absence of VEGF-A. Distant metastasis was associated with low intratumoral NMVD, high peritumoral LMVD, D2–40 positivity and absence of VEGF-A and VEGF-C expression. Recurrent cases presented low intratumoral NMVD, and absence of VEGF-A and VEGF-C expression. Low intratumoral NMVD, and D2–40 positive cells were found in all tumors of patients that died of the disease. In conclusion, although NMVD, LMVD, D2–40, VEGF-A, and VEGF-C could not predict the prognosis of MEC, intratumoral NMVD, peritumoral LMVD, D2–40 and VEGF-A expression seems play a role in the occurrence of a worse behavior in this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-289. doi:10.1158/1538-7445.AM2011-LB-289