tbuckley/cabot-search huggingface dataset:
PWE-085 CT Enterography Remains a Valuable Tool for the Assessment of Crohn’s Disease
Authors: K L White, C A Boyd, M Sapundzieski, J K Limdi
Journal: Gut (2013)

<h3>Introduction</h3> Advances in the immunopathogenesis of inflammatory bowel disease (IBD) coupled with bolder definitions of disease control have led to increasing reliance on imaging to characterise inflammation beyond the reach of the endoscope. Clinical activity indices underestimate biologic activity and cannot detect transmural disease. We aimed to assess the role of CT enterography (CTE) in assessing Crohn’s disease (CD). <h3>Methods</h3> A retrospective review of 406 consecutive CTE studies was performed between January 2009 and December 2012 at our institution. Clinical data including demographics, disease characteristics and therapy were obtained from electronic patient record review. Inflammatory markers, radiological investigations and ileocolonoscopy when performed within 90 days of CTE were recorded. CTE reports were recorded using accepted activity criteria- small bowel dilatation, stenosis, wall thickening, enhancement, mucosal irregularity, mesenteric inflammation, hypervascularity, lymph node enlargement, abscesses, fistulation and extraintestinal features. <h3>Results</h3> Of 175 patients with IBD at time of CTE, 154 had CD. Ninety-four of 154 patients were female<i>,</i> mean age 52 (range 16–87) and median term of follow up of 5 years (range 0–35). Abnormalities were noted in 100 scans; 56 had active non-stricturing, 42 active stricturing and 2 fibrostenotic disease. Within active groups, there were 10 fistulae and 3 abscesses in 11 patients. Ileo-colonoscopy was performed in 42 patients with 27 showing active inflammation and raised CRP in 38/96. Treatment was increased in 52% of the active non-stricturing group, 6/29 to azathioprine, 4/29 to biologics, 4/29 to methotrexate, 7/29 to steroids, 5/29 to surgery with no change in the remaining 48%, of whom 8/12 had inactive disease at ileo-colonoscopy and 16/24 normal CRP. In 57% of active stricturing patient treatment was increased in 1 to azathioprine, 11 to biologics, 5 to surgery. Twelve of 26 patients in this group had an elevated CRP and 10/13 had active colitis at ileo-colonoscopy. Of 53 normal CTE, treatment was escalated in 3 to methotrexate or azathioprine with colitis at colonoscopy and unchanged in 92%. <h3>Conclusion</h3> Concerns regarding potential cumulative effects of ionising radiation are valid but likely to be offset by changing technology and reduction in average doses of radiation. CTE has a role in well-selected patients with CD (e.g. age &gt; 50, very sick patients) identifying active disease and influencing meaningful therapeutic decisions. <h3>Disclosure of Interest</h3> None Declared.
Effects of riluzole (RZ) and ionizing radiation (IR) in metabotropic glutamate receptor-1 (GRM1) positive human melanoma
Authors: C. Green, D. Schiff, A. Khan, S. Goyal, J. Goydos, S. Chen, B. Haffty
Journal: Journal of Clinical Oncology (2009)

9083 Background: Melanoma has long been known to be relatively radio-resistant. GRM1 is a metabotropic glutamate receptor that has been detected in human melanoma cell lines and biopsies. Riluzole (RZ), a glutamate release inhibitor, has been shown to arrest GRM1 positive human melanoma cells in G2/M and sub-G1 phases of the cell cycle. The purpose of this study was to determine if RZ enhances the lethal effects of IR in human melanoma. Methods: ATP luminescence assays were performed. Clonogenic assays were performed and cell survival curves generated. Cell cycle analysis was performed utilizing flow cytometry. Western blot analysis was performed utilizing cleaved PARP and caspase-3 antibodies as markers of apoptosis. Results: Luminescence assays revealed 25uM Riluzole to be the necessary concentration for clonogenic assays. At 2Gy, there was a 48% reduction (p≤0.05) in cell survival in RZ-treated cells. At 4 Gy, there was a 19% reduction (p≤0.05) in cell survival in RZ-treated cells. No differences were seen at 6 and 8 Gy. Cell cycle analysis showed that the combination of IR and RZ was superior to IR alone in increasing the number of cells in sub-G1, which represents apoptotic death. Western blot analysis showed that the combination of IR and RZ showed yielded increased cleaved PARP and caspase-3 activity when compared to IR alone. Conclusions: Riluzole is a FDA approved drug that has long been used in ALS. It is relatively non-toxic and crosses the blood brain barrier. Our data shows that Riluzole in combination with radiation eliminates the radio-resistant shoulder of the C8161 survival curve. RZ and IR, as combination therapy are more lethal than IR or RZ alone in human melanoma, as demonstrated by flow cytometry and WB analysis. This data has promising implications for melanoma patients with brain metastases. No significant financial relationships to disclose.
THREE DIMENSIONAL ECHOCARDIOGRAPHIC ANATOMIC INTELLIGENCE APPROACH FOR FULLY AUTOMATED SIMULTANEOUS QUANTIFICATION OF LEFT VENTRICULAR AND ATRIAL VOLUMES
Authors: Diego Medvedofsky, Wendy Tsang, Masaaki Takeuchi, Lynn Weinert, Megan Yamat, Amit Patel, Ivan Salgo, David Prater, Victor Mor-Avi, Roberto Lang
Journal: Journal of the American College of Cardiology (2015)
Clinical Manifestations of AIDS in the Era of Pneumocystis Prophylaxis
Authors: Donald R. Hoover, Alfred J. Saah, Helena Bacellar, John Phair, Roger Detels, Roger Anderson, Richard A. Kaslow
Journal: New England Journal of Medicine (1993)

Among patients infected with human immunodeficiency virus type 1 (HIV-1), early and widespread use of prophylactic regimens against Pneumocystis carinii is changing the pattern of illnesses related to the acquired immunodeficiency syndrome (AIDS).
P1018 MARKERS OF COLLAGEN REMODELING DETECT CLINICALLY SIGNIFICANT FIBROSIS IN CHRONIC HEPATITIS C PATIENTS
Authors: M.J. Nielsen, K. Kazankov, D.J. Leeming, M.A. Karsdal, A. Krag, F. Barrera, J. George, H. Grønbæk
Journal: Journal of Hepatology (2014)
IMAGE-BASED COMPUTATION OF INSTANTANEOUS WAVE-FREE RATIO FROM ROUTINE CORONARY ANGIOGRAPHY: EVALUATION OF A HYBRID DECISION MAKING STRATEGY WITH FFR
Authors: Lucian Itu, Tiziano Passerini, Elisabeta Badila, Lucian Calmac, Diana Zamfir, Dana Penes, Rodica Niculescu, Emma Weiss, Laszlo Lazar, Marius Carp, Alexandru Itu, Constantin Suciu, Puneet Sharma, Bogdan Georgescu, Dorin Comaniciu
Journal: Journal of the American College of Cardiology (2016)
Abstract 1348: Expression of Bone Morphogenetic Protein-6 closely related to Interleukin-10 in renal cell carcinoma and BMP-6 induced IL-10 <i>in vitro</i>
Authors: Jae-Ho Lee, Geun Taek Lee, Seok Joo Kwon, Wun-Jae Kim, Isaac Yi Kim
Journal: Cancer Research (2010)

Abstract Primary kidney cancers are the third most common genitourinary tumor in USA in 2008. The majority of kidney tumors (80-85%) are classified as RCC. Since RCCs are generally resistant to chemotherapy and hormonal therapy, only a few therapeutic options are available, such as immunotherapy and molecular targeted therapy when surgical treatment is not available. Bone morphogenetic proteins (BMPs) are the largest group of proteins in the TGF-β family. BMPs are known to have critical role in the various kinds of developmental processes and frequently over-expressed in the various cancers including prostate, bladder and kidney. Recently, BMP-6 has been reported to play a role in the immune system, inhibit T cell proliferation and activate the macrophages. Interleukin-10 (IL-10) is a type II cytokine and has anti-inflammatory function in the immune system. It is reported that IL-10 or IL-10 receptor expression is related to the metastasis of RCC. In this study, we found that BMP-6 expression level is tightly co-related to anti-inflammatory cytokine IL-10 expression (P &amp;lt; 0.001) in 74 human RCC tissue samples. In vitro assay, BMP-6 induced IL-10 in dose and time dependent manners in the mouse peritoneal macrophage and RAW 264.7 cell line. This induction was inhibited by cycloheximide, not by Actinomycin D. IL-10 induction was mediated by the canonical Smad dependent BMP-6 signal pathway. In the IL-10 promoter luciferase activity assay, BMP-RII, ALK-2/3, Smad 5 and Smad 4 were responsible for the BMP-6 induced IL-10 expression. Smad 5 bound to the −800 to −600 region of IL-10 promoter in the ChIP assay. Also Smad-independent STAT3 pathway is required for the IL-10 induction. STAT3 also bound to the −800 to −600 region in ChIP assay and interacted with Smad 5. In conclusion, BMP-6 expression related with IL-10 in RCC and the direct induction of IL-10 by BMP-6 was observed in macrophages. Thus, BMP-6 seemed to induce IL-10 in RCC and modulated tumor immune environment. 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 1348.
FDG PET/CT Findings in a Rare Case of Giant Fibrovascular Polyp of the Esophagus Harboring Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
Authors: Volkan Beylergil, Marc Z Simmons, Gary Ulaner, Joseph Jurcic, Hanina Hibshoosh, Jorge A Carrasquillo
Journal: Clinical Nuclear Medicine (2014)

A 70-year-old man with a history of chronic lymphocytic leukemia (CLL) underwent FDG PET/CT scan, which revealed a large polypoid soft tissue lesion in the esophagus with peripheral FDG avidity. An endoscopic biopsy revealed inflammatory changes with scattered CLL cells. The final histopathology demonstrated an 18-cm long and 4-cm wide giant fibrovascular polyp that was removed in 2 pieces. The polyp was composed of atypical adipose tissue with scattered giant cells and spindle-shaped cells as well as foci of CLL. Mouse double minute 2 homolog amplification was noted by fluorescence in situ hybridization diffusely in the giant polyp consistent with well-differentiated liposarcoma in a giant fibrovascular polyp.
Abstract 5669: Design and synthesis of membrane type matrix metalloproteinase (MT-MMP) targeted anti-tumor agents.
Authors: Robert A. Falconer, Ahmed M. Youssef, Javier Gimenez Warren, Goreti R. Morais, Andrew Mitchell, Steve D. Shnyder, Jason H. Gill, Laurence H. Patterson, Paul M. Loadman
Journal: Cancer Research (2013)

Abstract Design and synthesis of membrane type matrix metalloproteinase (MT-MMP) targeted anti-tumor agents Membrane-type matrix metalloproteinases (MT-MMPs) are highly active in tumors, but absent or inactive in normal tissues. MT-MMPs are known to be elevated in the majority of human tumors and to be central to tumor invasion and angiogenesis. Our objective has been to design inactive prodrugs that are converted to a potent drug by selected MMPs within the tumor microenvironment. We report the design and synthesis of a series of peptide-based conjugates of azademethylcolchicine (a potent colchicine analogue) designed to be selectively cleaved by MT-MMPs in the tumor microenvironment. Azademethylcolchicine was attached to the peptide C-terminus, while the N-terminus is protected from non-specific cleavage by exopeptidases through a masking group. A series of N-terminal masking groups, including unnatural amino acids, substituted aromatic groups, alkyl spacers and more complex endcaps was employed. Insights have been gained into the MT-MMP peptide recognition sequence and the relative importance of individual amino acids with regards MMP-selectivity. The P2’ position in particular has been extensively studied through substitution by both natural amino acid and unnatural amino acids. We have investigated the efficiency of hydrolytic cleavage of these conjugates to release the active agent in both tumor and normal tissues. Results indicate significant effects of P2’ amino acid substitution upon stability and conversely activation in tumor and normal tissues (liver, kidney, lung, plasma), with half-lives of hydrolysis ranging from 2-60 min in tumor and 3-300 min in normal tissues. In conclusion, a series of peptide-based prodrug conjugates of azademethylcolchicine was synthesized. Hydrolytic activation of these prodrugs in tumor tissue was rapid compared to liver and other normal tissues. From this screen, ICT-2588, which includes tyrosine at the P2’ position, emerged as the agent with a hydrolytic cleavage rate most suited for further evaluation as a tumour activated peptide-based conjugate. Citation Format: Robert A. Falconer, Ahmed M. Youssef, Javier Gimenez Warren, Goreti R. Morais, Andrew Mitchell, Steve D. Shnyder, Jason H. Gill, Laurence H. Patterson, Paul M. Loadman. Design and synthesis of membrane type matrix metalloproteinase (MT-MMP) targeted anti-tumor agents. [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 5669. doi:10.1158/1538-7445.AM2013-5669
Encourage: the Use in Routine Practice of Bevacizumab in First-Line Therapy for Patients with Ovarian Cancer– a Gineco Prospective Cohort Study
Authors: D. Berton-Rigaud, F. Selle, I.L. Ray-Coquard, A. Floquet, R. Largillier, A. Hardy-Bessard, D. Jaubert, C. Roemer-Becuwe, L. Venat-Bouvet, A. Lesoin, E. Guardiola, J. Alexandre, M. Provansal, E. Blot, N. Achour, E. Pujade-Lauraine
Journal: Annals of Oncology (2014)
Abstract LB-277: Global translational regulation by miR-520c
Authors: Krystyna Mazan-Mamczarz, Frank Zhao, Bojie Dai, James Steinhardt, Ronald B. Gartenhaus
Journal: Cancer Research (2012)

Abstract MicroRNAs (miRNAs) are endogenous small non-protein-coding RNAs that control a variety of cellular processes by modulating protein expression. Many studies have focused on the role of microRNAs in cancer development and age-related diseases, but the cellular mechanisms by which microRNAs influence aberrant cell growth are still poorly understood. We found that overexpression of a miR-520c-3p precursor decreased global gene translation, and induced senescence as measured by monitoring beta-galactosidase activity and other senescence markers. To better understand the mechanisms underlying miR-520c-3p mediated global translational repression, we performed translational profiling of mRNA isolated from polysomal fractions. We identified subsets of cancer-related genes with repressed translation after overexpression of miR-520c-3p. Interestingly, among them we found eukaryotic translation initiation factor 4 gamma 3 (eIF4G3), a key component of the cap-dependent translation regulation complex (eIF4F). While increases in miR-520c-3p did not change eIF4G3 mRNA abundance, there was a significant reduction in eIF4G3 protein synthesis. The specific repressive influence of miR-520c-3p on eIF4G3 was confirmed by employing heterologous reporter constructs bearing the 3′ untranslated region (3′UTR) of eIF4G3 mRNA. In addition, either miR-520c-3p overexpression or eIF4G3 knockdown, led to decreased eIF4E association with the translation initiation complex as measured by 7-methyl-GTP cap analog pull down, and diminished colony formation in lymphoma cells, as assessed by clonogenic assays. Finally, our findings that, diffuse large B cell lymphoma (DLBCL) cells express low levels of miR-520c-3p with reciprocally high eIF4G3 protein levels, and that TMA analysis revealed significantly higher eIF4G3 expression in patient DLBCL samples compared to normal GCB cells, supports the role of these molecules in the dysregulation of protein synthesis present in NHL. In summary, we demonstrated that overexpression of mir-520c-3p can suppress tumor growth by decreasing global protein translation and inducing senescence in DLBCL cells, and that miR-520c-3p elicits these actions by repressing eIF4G3 expression. Repressed global gene translation and premature senescence blocks cell proliferation, and together function as tumor suppressor mechanisms. Therefore, inhibition of translation and induction of senescence by miRNAs and/or small molecule inhibitors that target eIF4G3 is an innovative strategy for lymphoma therapy. 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 LB-277. doi:1538-7445.AM2012-LB-277
Abstract 4283: Src phosphorylates splicing factor 45 (SPF45) and regulates SPF45 nucleocytoplasmic shuttling, cell migration and invasion.
Authors: Yuying Liu, Lashardai Neniara Conaway, Jennifer Rutherford Bethard, Amber Thompson Bradley, Scott Eblen
Journal: Cancer Research (2013)

Abstract Src phosphorylates splicing factor 45 (SPF45) and regulates SPF45 nucleocytoplasmic shuttling, cell migration and invasion Yuying Liu1, LaShardai Conaway1, Jennifer Rutherford Bethard1, Amber Thompson Bradley1 and Scott T. Eblen1,2 From Department of Cell and Molecular Pharmacology and Experimental Therapeutics1 and the Hollings Cancer Center2 Medical University of South Carolina, Charleston, SC, 29425 SPF45 is a bifunctional protein involved in splicing and DNA repair and is overexpressed in several forms of cancer. Previously, we have shown that SPF45 overexpression regulates ovarian cancer cell proliferation and adhesion in a MAP kinase phosphorylation-dependent manner. In this study, we investigated novel roles of SPF45 and their regulation by the tyrosine kinase Src. We show by cell fractionation that endogenous SPF45 localizes in both the nucleus and cytoplasm and that exposure of cells to UV irradiation or osmotic shock increased SPF45 cytoplasmic accumulation. Consistent with this result, heterokaryon assays using SKOV-3 cells stably expressing Myc-SPF45 showed that SPF45 shuttles between the nucleus and cytoplasm and that pretreatment of the cells with the Src family kinase inhibitor PP2 inhibited nucleocytoplasmic shuttling. Src strongly induced SPF45 tyrosine phosphorylation and co-immunoprecipitated with SPF45 after co-transfection into COS-1 cells. Src phosphorylated SPF45 in vitro on five tyrosine residues (Y100, Y108, Y194, Y214 and Y246), as determined by mass spectrometry. Sequential mutation of these sites to phenylalanine inhibited SPF45 tyrosine phosphorylation in cells co-transfected with Src, with mutation of all 5 sites (Myc-SPF45-Y5F) completely inhibiting SPF45 tyrosine phosphorylation. Myc-SPF45-Y5F stably expressed in SKOV-3 cells showed reduced nucleocytoplasmic shuttling compared to wild type Myc-SPF45. SKOV-3-Myc-SPF45 cells demonstrated enhanced migration and invasion compared to vector control cells, while SKOV-3-Myc-SPF45-Y5F cells migrated significantly less than SKOV-3-Myc-SPF45 cells. These data are the first to show that SPF45 is a shuttling protein, a Src substrate, and that Src phosphorylation of SPF45 regulates nucleocytoplasmic shuttling and SPF45-induced cell migration and invasion. Citation Format: Yuying Liu, Lashardai Neniara Conaway, Jennifer Rutherford Bethard, Amber Thompson Bradley, Scott Eblen. Src phosphorylates splicing factor 45 (SPF45) and regulates SPF45 nucleocytoplasmic shuttling, cell migration and invasion. [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 4283. doi:10.1158/1538-7445.AM2013-4283
Utility of ovarian cancer screening in women with <i>BRCA</i> mutations
Authors: S. N. Lewin, Y. Kemel, K. Kosarin, J. Hansen, M. E. Robson, K. Offit, R. R. Barakat, N. D. Kauff
Journal: Journal of Clinical Oncology (2008)

5531 Background: Several practice guidelines have suggested that BRCA mutation carriers undergo ovarian cancer screening with transvaginal ultrasound (TVU) and serum CA125 if risk-reducing salpingo-oophorectomy (RRSO) has not been performed. Limited data, however, exists examining the efficacy of ovarian cancer screening in this population. Methods: Records from women > 30 years of age, with deleterious BRCA mutations, who enrolled on one of three prospective follow-up studies at time of genetic testing were reviewed. For women who had ovaries in-situ at time of study enrollment, information on participation in ovarian cancer screening with TVU and CA125, as well as incidence of abnormalities, was obtained from structured questionnaires completed annually by the participants. All self- reported cancer diagnoses were confirmed by review of pathology reports. In order to prevent bias caused by the detection of prevalent ovarian pathology, only patients who reported screening for greater than 1 year following receipt of genetic test results are included in this report. Results: From 10/1/95 - 1/31/06, 545 women > 30 years of age with a deleterious BRCA mutation and ovaries in-situ were ascertained. 120 of these women reported participating in ovarian cancer screening for at least one year following receipt of genetic test results. During a median 3.2 yrs follow-up, 36 (30%) women reported at least 1 abnormality on either TVU or CA125 which required short interval follow- up. 7 (6%) women had persistent abnormalities which lead to surgery. Of these, 4 cancers were diagnosed after a mean of 4.7 yrs (range 3.4 to 5.0 yrs) of screening. Stages included: IA grade 3 (1), IC (2) and IIIA (1). Of 54 women who elected to ultimately undergo RRSO after screening for at least a year, one occult cancer (2%) was found after 5.6 years of screening (an unstaged fallopian tube carcinoma that was at least Stage IIa). Conclusions: These findings suggest that ovarian cancer screening via transvaginal ultrasound and/or CA-125 can detect early stage BRCA-associated gynecologic malignancies. However, given that two of five cancers found in this series were diagnosed at an advanced stage, caution is warranted before ovarian cancer screening can be recommended as a viable long-term alternative to RRSO. No significant financial relationships to disclose.