tbuckley/cabot-search huggingface dataset:
Abstract 4325: Monoclonal antibodies to transmembrane proteins.
Authors: Michael C. Brown, Ross Chambers, Dale V. Onisk, Tony R. Joaquim, Lewis J. Stafford, Klaus Lindpaintner, Daniel Keter, James W. Stave
Journal: Cancer Research (2013)

Abstract Transmembrane proteins, including multipass transmembrane proteins like GPCRs and ion channels, are important targets for therapeutic monoclonal antibody (mab) discovery. Therapeutic antibodies to this class of proteins are generally targeted to extracellular domains displayed on the surfaces of living cells. Challenges associated with developing antibodies to this class of targets are small numbers of extracellular amino acids, membrane-dependent protein conformation, difficulty in expression at high levels, high amino acid sequence homology of human and mouse proteins, and post-translational modifications. DNA immunization strategies with full-length constructs and high throughput flow cytometry screening of mab binding to transfected and control cells was used to generate and identify large numbers of mabs to CXCR4 and ADORA2A (GPCRs) and CD20 (a tetraspan membrane protein). Panels of mabs were generated for all 3 targets with low numbers of hybridoma fusions. For each target the mab gene sequences were shown to be unique and contain levels of somatic hypermutation comparable to existing benchmark therapeutic antibodies. Epitope mapping with mutant proteins identified diverse patterns of reactivity including known and novel specificities. Functional assays including apoptosis and receptor modulation (calcium flux and cAMP modulation) further demonstrated that the technical approach generated diverse panels of antibodies that exhibit functional activity as good or better than existing benchmark therapeutic antibodies Citation Format: Michael C. Brown, Ross Chambers, Dale V. Onisk, Tony R. Joaquim, Lewis J. Stafford, Klaus Lindpaintner, Daniel Keter, James W. Stave. Monoclonal antibodies to transmembrane proteins. [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 4325. doi:10.1158/1538-7445.AM2013-4325
DD-06 * POTENTIATING THE THERAPEUTIC EFFICIENCY OF THE ALKYLATING CHEMOTHERAPY TEMOZOLOMIDE IN PATIENTS WITH GLIOBLASTOMA
Authors: A. Kolb, C. Watts, S. Piccirillo
Journal: Neuro-Oncology (2014)

Glutamate is the most prominent excitatory neurotransmitter of the brain. Due to its pivotal role, deregulations of the glutamate metabolism have been implicated in various CNA diseases. System xc- (SXC), an L-cystine/L-Glutamate antiporter represents the primary non-vesicular route of glutamate release. SXC is upregulated under amino acid deprivation, xenobiotic exposure and oxidative stress. GBM depends on L-cystine influx by SXC activity, to uphold a sufficient Glutathione level. Glutathione is a neuroprotective peptide involved in removal of xenobiotics, like therapeutic drugs. L-cysteine is essential for its synthesis. SXC is highly expressed in Glioblastoma Multiforme (GBM), the most common type of brain malignancy with a median survival of only 14 months. GBM has proven to be highly resistant to therapy. Thusly, potentiating the efficacy of Temozolomide by blocking SXC might lead to an increase in median survival. We are investigating expression of SXC in GBM -in surgical specimen and patient derived cell lines- and the effect of Sulfasalazine (SSZ) on cell survival. SSZ is a FDA-approved SXC antagonist. SXC expression in surgical specimen of GBM and thereof derived cell lines was investigated on mRNA and protein level. Since our results reaffirmed expression of SXC, cell lines were treated in vitro with either SSZ, TMZ or concomitantly. Concomitant treatment resulted in a continuous decrease in viability over the course of 30 days. Survival was significantly decreased when compared to control, SSZ or TMZ alone, without any rescue efffect. In conclusion, the evidence shows a strong correlation between prolonged survival and concomitant use, suggesting a heightened sensitivity to chemotherapy, conveyed by blocking of the system xc- antiporter. Thusly, pharmacokinetics of SSZ have been analysed to assess brain penetration. In future work, the efficacy of concomitant treatment with SSZ and TMZ will be evaluated in vivo to indicate whether there would be any clinical utility.
Independent Radiological Evaluation of Objective Response Early Tumor Shrinkage, and Depth of Response in FIRE-3 (AIO KRK-0306)
Authors: V. Heinemann, D. Modest, L. Fischer von Weikersthal, T. Decker, A. Kiani, U. Vehling-Kaiser, S-E. Al-Batran, T. Heintges, C. Lerchenmüller, C. Kahl, G. Seipelt, F. Kullmann, M. Stauch, W. Scheithauer, S. Held, C. Giessen, M. Möhler, A. Jagenburg, S. Stintzing
Journal: Annals of Oncology (2014)
Abstract LB-36: Circulating epithelial tumor cells are responsive to BMP-2
Authors: Franziska Bähring, Elena Reber, Ute Müller, Roland Kilper, Kathleen Wagner, Andreas Hochhaus, Joachim H. Clement
Journal: Cancer Research (2011)

Abstract Aims: Bone morphogenetic proteins (BMP) play an important role in early embryonic development as well as in organ homeostasis and in tumorigenesis. We could show previously that BMP-2 enhance migratory and invasive properties of tumor cells. Furthermore, BMP-2 affects the expression of genes which are involved in the regulation of apoptosis. A crucial step in metastasis formation is the liberation of tumor cells from the primary site, the entrance into circulation and the long-lasting persistence in the peripheral blood. Therefore we asked whether BMPs might contribute to the vitality of circulating tumor cells. Methods: Leukocytes and circulating epithelial cells from the peripheral blood of breast cancer patients were labelled with fluorescent antibodies and magnetically enriched with the MACS® system. After separation of single vital cells with the aureka® device, a single cell multiplex RT PCR was performed using the AmpliGrid system. The PCR products were analysed by urea-polyacrylamide gel electrophoresis. For real-time single cell PCR demonstrating the expression level of selected genes the Fastlane system (Qiagen, Hilden) was used. Localization of phosphorylated receptor Smads was analysed by laser scanning microscopy after one hour incubation with 100 ng/ml BMP-2. Results: Circulating epithelial cells were identified by using the cell surface antigen EpCam. Vital EpCam-positive cells were picked and subjected to multiplex RT-PCR covering 5 components of the BMP signaling cascade as well as RPL13A for control. 121 of 265 selected cells expressed RPL13A. These cells were used for further analysis. Most of these cells expressed BMP-2 (54%), BMPR-IA (46%), BMPR-IB (82%). Transcripts of the type II receptor BMPR-II (35%) and the putative BMP antagonist BMP-3 (25%) were presen to a lower extend. The expression level of BMP-2 was comparable in individual EpCam-positive cells, thus at least an autocrine stimulation of the BMP signaling pathway can be assumed. For studying the responsiveness of circulating epithelial cells towards a BMP stimulus these cells were enriched from peripheral blood and incubated with BMP-2. Vital cells showed a predominant nuclear staining for pSmad1 demonstrating a functional BMP signalling network. Conclusion: We show that key components of the BMP signaling pathway are expressed in leukocytes and epithelial cells in the peripheral blood of breast cancer patients. This indicates that the BMP signaling network potentially contributes to the activity and survival of circulating epithelial cells. This work was supported by the Dr. Rainald-Stromeyer-Stiftung 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-36. doi:10.1158/1538-7445.AM2011-LB-36
Uniform Detection of Immunoglobulin-Gene Rearrangement in Benign Lymphoepithelial Lesions
Authors: Andrew Fishleder, Raymond Tubbs, Bonnie Hesse, Howard Levine
Journal: New England Journal of Medicine (1987)

The term "benign lymphoepithelial lesion" is used to describe the salivary-gland lymphocytic infiltration and epithelial changes typically found in association with Sjögren's syndrome. We used Southern blot hybridization techniques to examine the immunoglobulin genes in salivary-gland tissue derived from eight patients with benign lymphoepithelial lesions. Three of these patients had intrasalivary non-Hodgkin's lymphoma complicating the lesions, whereas the lesions in the remaining five were all histologically benign. Ten samples from the eight patients all revealed rearrangement of both the heavy-chain and light-chain immunoglobulin genes. In one of the patients in whom non-Hodgkin's lymphoma involved both the salivary-gland lesion and an ipsilateral lymph node, the rearrangements of the heavy-chain and light-chain immunoglobulin genes detected at the two sites were identical. One other patient had two distinct benign lymphoepithelial lesions removed two years apart. The rearrangements of the heavy-chain as well as the kappa light-chain genes detected in these two lesions were entirely different. These data suggest that B-cell clonal expansion has an integral role in the pathophysiology of the benign lymphoepithelial lesion and may explain the increased incidence of lymphoma noted in association with this disorder.
METABOLIC STUDIES IN MONGOLISM
Authors: ALEXANDER SIMON, CHARLES LUDWIG, JOHN W. GOFMAN, G. HAMILTON CROOK
Journal: American Journal of Psychiatry (1954)

1. In order to study thyroid and lipid function in mongolism, the levels of serum protein-bound iodine, cholesterol, and the fraction of Sf 12-20 molecules of lipoproteins were studied in a group of 74 mongoloid patients, and these were compared with the findings in normals and with a group of 18 cases diagnosed as "undifferentiated mental deficiency." 2. There was no significant difference in the serum protein-bound iodine levels between mongoloid children and "controls" of the same age. 3. Mentally retarded children, whether the diagnosis is mongolism or undifferentiated mental deficiency, have significantly higher serum cholesterol levels than normal children. 4. The most marked differences between mongoloids, normal, and control children occur in the level of large molecule lipoproteins of the Sf 12-20 class, the mongoloids being highest, the cases of undifferentiated mental deficiency intermediate, and the normals lowest.
Abstract 1655: Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines.
Authors: Yoshinari Okada, Shunsuke Kato, Yasuhiro Sakamoto, Takayuki Oishi, Chikashi Ishioka
Journal: Cancer Research (2013)

Abstract Autophagy is a stress-induced cellular reaction in cancer cells. Recent studies showed that cyclin dependent kinase inhibitor proteins, such as p27 or p16, also induced cytoprotective autophagy in cancer cells. However, it is not clear whether small molecule CDK inhibitors also induce autophagy in solid cancer cells. In this study, we revealed that CDK4 inhibitor and a broad-range CDK inhibitor (flavopiridol) induced autophagy in some solid cancer cell lines, but not all. The autophagy induced by CDK4 inhibitors was observed in BT474, MDA-MB435S, SKBr3 (derived from breast cancer), A431 (derived from lung cancer) and SW480 (derived from colorectal cancer), While it was not observed in MCF7, MDA-MB231 (derived from breast cancer), NCI-N87 (derived from gastric cancer) and KMST-6 (derived from fibroblast). In the cell lines which were induced autophagy by CDK inhibitors, the combination of a CDK4 inhibitor and an autophagy inhibition, by either chloroquine or knockdown of ATG5 or BECN1, induced apoptosis. However it did not induce apoptosis in the cell lines which were not induced autophagy by CDK4 inhibitor. From these results, the autophagy induced by CDK4 inhibitor mimic the stress-induced autophagy in some solid cancer cell lines. The combination of a small-molecule CDK inhibitor and an autophagy inhibitor is a synthetic lethal interaction and could become a new antitumor strategy in solid tumors which are induced cytoprotective autophagy by CDK inhibitors. Citation Format: Yoshinari Okada, Shunsuke Kato, Yasuhiro Sakamoto, Takayuki Oishi, Chikashi Ishioka. Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines. [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 1655. doi:10.1158/1538-7445.AM2013-1655
P204 Reducing antigen exposure in pigeon breeders. Wearing a mask is a sign of disease
Authors: K McHugh, I Fraser, S Bourke, C McSharry, P Lynch, K Anderson
Journal: Thorax (2013)

<h3></h3> Advice to pigeon breeders from the British Pigeon Fanciers Medical Research website includes methods to reduce dust exposure: as well as increasing loft ventilation, it recommends that a respirator is worn while in the loft. A field survey of the use of masks for this purpose found up to 40% usage amongst breeders (n = 258). Studies in small numbers of HP patients demonstrated reducing symptom response following inhalation provocation tests as well as reducing serum antibody levels (1). Despite the potential benefit of wearing masks, and the apparent willingness of pigeon fanciers to do this, little is known about their protective value in HP. The aim of this study is to compare survey results since 1991, and to examine the relationship between diagnosis of pigeon breeder’s disease (PBD), serology, spirometry and mask wearing. Our 1997 survey (n = 252) showed that 51% would use a mask. In our 2013 survey (n = 188), we had a response of 54%. Those wearing a mask have higher IgG (mcg/ml) antibody levels (interquartile range 0.92–16.33 median 4.96 –v- 3.02–17.04 median 8.55, p = 0.047). Questionnaire symptom responses, spirometry, as well as useful radiology (CT scanning) or biopsy were used to grade the likelihood of PBD as unlikely (n = 99), maybe (57) or likely (32). Mask wearing was associated with likelihood of PBD (p = 0.068). Those with symptoms (n = 46) or minimal symptoms (n = 38) performed spirometry. Analysis showed an apparent trend amongst subjects with a restrictive defect to be more marked amongst mask wearers–70% (n = 16) being moderate/severely restricted–compared to 43% non mask wearers (Chi-sq = 2.62, p = 0.105). We interpret these findings as evidence that mask wearing is much more likely after symptoms have appeared in pigeon breeders: not the pattern we expected of mask wearing (or dust avoidance) to prevent the development of the disease. Paradoxically, mask wearing in pigeon breeders may also be an unreported sign of PBD. <h3>References</h3> Hendrick, D J (1981) Protective value of dust respirator in extrinsic alveolitis: clinical assessment using inhaltion provocation tests. <i>Thorax.</i><b>36: 917–921</b>
Abstract 1578: Small molecule HIF-2a inhibitors down regulate its activity in vivo and ameliorate the vhl zebrafish phenotype.
Authors: Ana Metelo, Li Xiang, Rania Baker, Lee Kamentsky, Anne Carpenter, Randall Peterson
Journal: Cancer Research (2013)

Abstract Hypoxia Inducible Factor (HIF) target genes are involved in several cellular processes including angiogenesis, erythropoiesis, metabolism and stem cell proliferation. The von Hippel-Lindau (VHL) tumor suppressor protein targets HIF for degradation in conditions of normal oxygen tension. Loss-of-VHL leads to constitutive expression of HIF. We have discovered small molecules that repress HIF-2α translation by enhancing the binding of Iron-Regulatory Protein 1 (IRP1) to the Iron-Responsive Element (IRE) within the 5’-UTR of HIF-2α mRNA and showed that these small molecules specifically down-regulate HIF-2α expression in vitro. To validate the HIF-2α inhibitors in vivo, first we tested their efficacy to inhibit acute hif induction in wild-type (wt) zebrafish embryos challenged with the hypoxia mimetic DMOG. Treatment of wt embryos with 100μM of DMOG up-regulated the expression of zebrafish HIF-target genes, such as vascular endothelial growth factor (vegf), erythropoietin (epo) and prolyl-hydroxylase 3 (phd3). Pre-treatment of embryos with the small molecule HIF-2α inhibitor 76 (10nM) significantly decreased the DMOG-induced up-regulation of HIF target genes and resulted in decrease of DMOG-induced erythrocytosis and blood vessel sprouting. Furthermore, we tested the efficacy of this HIF-2α inhibitor in a vhl zebrafish model (homozygougous mutants harbouring inactivating vhl mutations), which recapitulates aspects of human VHL disease (erythrocytosis, abnormal vascular proliferation in sites such as retina and brain, early lethality). Treatment with inhibitor 76 (10nM, 100nM and 1μM) down regulated the expression of the HIF-target genes phd3, epo and vegf in a dose response manner and rescued the erythrocytosis and sprouting phenotype of vhl embryos. To image and quantify the blood vessel abnormalities of vhl embryos, we generated a Fli-GFP::vhl+/- line and showed that compound 76 improves the abnormal connections between the intersegmental vessels of the Fli-GFP::vhl embryo tail, as well as their human hemangioblastoma-resembling brain vessel proliferation. Finally, we showed that treatment of vhl embryos with compound 76 rescues early lethality. Our data demonstrate that HIF-2α inhibitor 76 is active in vivo at low concentrations and encourage further development and preclinical testing of this HIF-2α inhibitor for treatment of VHL-associated lesions, such as renal cell carcinoma, hemangioblastoma and neuroendocrine tumors. Citation Format: Ana Metelo, Li Xiang, Rania Baker, Lee Kamentsky, Anne Carpenter, Randall Peterson. Small molecule HIF-2a inhibitors down regulate its activity in vivo and ameliorate the vhl zebrafish phenotype. [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 1578. doi:10.1158/1538-7445.AM2013-1578
Preoperative Treatment with Radiochemotherapy for Locally Advanced Gastroesophageal Junction (GEJ) Cancer and Unresectable Locally Advanced Gastric Cancer
Authors: Oblak Irena, Anderluh Franc, Velenik Vaneja, But-Hadzic Jasna, Secerov-Ermenc Ajra, Jeromen Ana, Ratosa Ivica
Journal: Annals of Oncology (2014)
MATURATIONAL CHANGES AND REFERENCE VALUES FOR TRICUSPID ANNULAR PLANE SYSTOLIC EXCURSION (TAPSE) FROM BIRTH TO ONE-YEAR CORRECTED AGE: RIGHT VENTRICULAR SYSTOLIC FUNCTION IN PRETERM NEONATES
Authors: Philip Levy, Meghna Patel, Aaron Hamvas, Gautam Singh
Journal: Journal of the American College of Cardiology (2016)
Abstract LB-319: Microarray CGH profiling predicts survival after a diagnosis of epithelial ovarian cancer and identifies novel candidate therapeutic targets
Authors: Christopher Jones, James Morris, Tanya Sher, Sumera Ghani, Ian J. Jacobs, Estrid Hogdall, Jan Blaakær, Susanne Kruger-Kjaer, Lise Christensen, Claus Hogdall, Susan Ramus, Simon Gayther, Alan MacKay
Journal: Cancer Research (2011)

Abstract There is a need to identify novel therapeutic targets and better prognostic markers for ovarian cancer. Previous studies have shown that somatic genetic alterations are associated with clinicopathological features of cancers, and array comparative genomic hybridisation (aCGH) analysis is an excellent tool for providing detailed genetic profiles of a tumour from archival material. In this study we performed aCGH analysis on 116 primary stage III/IV serous ovarian adenocarcinomas and used a combined univariate and iterative SVM-based approach to identify regions of chromosomal alteration whose copy number status is associated with survival. Cases were stratified according to survival probability (Pr), identifying 39 good survivors (Pr&amp;lt;0.33) and 39 poor survivors (Pr&amp;gt;0.67). We then identified genomic regions of either common gain/loss in all 116 cases, or in which copy number status differed between the extremes of survival. A sub-set of data from these regions in the 78 cases at the extreme ends of survival was supplied to an iterative Support Vector Machine (SVM) routine, which ranked regions by their contribution to accurate survival classification and refined their boundaries. Hierarchical cluster analysis confirmed the potential of the minimal intervals of these regions to predict survival. A SVM was then validated with independent data and shown to be able to accurately classify survival. The highest-ranked chromosome regions contain candidate genes that may represent prognostic markers and/or therapeutic targets for ovarian cancer. One region, containing the CCNE1 gene, is frequently amplified in tumours and has recently been shown to be a prognostic marker for ovarian cancer in other studies. Other regions contain genes involved in pathways that stimulate ovarian cancer cell growth, motility and drug resistance. This study demonstrates the power of tumour profiling in cancer samples to identify prognostic signatures and clues to the underlying biology of tumour development, if the study design is rigorous in the selection of tightly stratified patient subgroups and in the application of the correct computational methodologies. These results require validation in larger sample sizes; but the ability to perform whole genomic profiling in formalin fixed tissues and the establishment of consortia to bring together multiple studies (e.g. the international ovarian cancer association consortium) makes this possible. 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-319. doi:10.1158/1538-7445.AM2011-LB-319
Preterm Ovarian Hyperstimulation
Authors: Ihsan Esen, Fatma Demirel
Journal: New England Journal of Medicine (2015)

A 3-month-old female infant presented with swelling of the external genitalia. She had been born prematurely, at 27 weeks of gestation. After discharge, her mother noted the gradual development of genital swelling. Ultrasonography of the abdomen revealed two cysts on the right ovary.
Mitral-Valve Disease
Authors: James B. Dealy
Journal: New England Journal of Medicine (1956)

WITH the advent of commissurotomy and valvuloplasty for the surgical correction of mitral stenosis, it became of more than academic interest to differentiate the two components of combined mitral-valve disease. Early attempts to do this were frustrated by the paucity of data against which the accuracy of radiologic impressions could be checked, especially in patients who defied classification by any technic as having stenosis or insufficiency as their incapacitating lesion.Many patients, subsequently shown to have widely different valve sizes, presented confusing and overlapping x-ray changes (Fig. 1.). As a result, the validity of x-ray opinion was limited largely to . . .