tbuckley/cabot-search huggingface dataset:
PTU-006 Large colonic polyps detected during bowel cancer screening—a retrospective review of treatment and outcomes: Abstract PTU-006
Authors: H Fellows, U Meagher, R Tighe
Journal: Gut (2010)

<h3>Introduction</h3> Bowel cancer is the third most common cancer in the UK, with approximately 16 100 deaths per annum. The Norfolk and Norwich University Hospital was one of the first sites in the country to introduce the bowel cancer screening (BCS) programme. It offers men and women aged between the ages of 60 and 69 an initial screening via a faecal occult blood test. Those with an abnormal result are then offered a colonoscopy. Large (&gt;2 cm) polyps are uncommon in routine practise however with the development of the BCS programme are now more readily encountered. <h3>Methods</h3> To assess the success and safety of endoscopic resection of large (&gt;2 cm) colorectal polyps in the context of the BCS programme. Records of all patients who had a polyp &gt;2 cm were identified using the BCS database. We analysed data from a 3-year period starting from July 2006 until July 2009. We looked at polyp location, morphology, completeness of resection, complications and histological staging. <h3>Results</h3> 135 polyps &gt;2 cm were detected in 127 patients with a mean size of 3 cm (spread 2–7 cm). 17.8% (24/135) were thought to be invasive by the endoscopist and all of these were biopsied. 12.5% of these biopsied polyps were found to be adenocarcinoma/carcinoma in situ. 11.9% (16/135) of all polyps were adenocarcinoma. 31.9% (43/135) of polyps were sessile, and 68.9% (92/135) were pedunculated. 94.1% (127/135) of polyps were left sided. 82.2% (111/135) of polyps were removed at the time of the initial endoscopy. Of these 22.5% were sessile and 77.5% pedunculated. 20% of the sessile polyps had further treatment by means of either surgery (12%,3/3 benign disease) or repeat polypectomy (8%) for residual polyp tissue. In comparison 8.1% of pedunculated polyps went on to have either surgery (5.8%, 4/5 adenocarcinoma) or repeat polypectomy (2.3) for residual polyp tissue. There were no carcinomas detected in those polyps measuring &gt;5 cm. However the greatest percentage of adenocarcinomas were found in pedunculated polyps measuring 4049 mm. Three patients required endoscopic therapy for bleeding at the time of polypectomy and two patients were admitted as a precaution. Three patients had immediate bleeding following polypectomy which was controlled endoscopically at the time of initial endoscopy. Two of these patients were admitted overnight as a precaution. There were no cases of perforation, no late bleeds and no readmissions. <h3>Conclusion</h3> Our series demonstrates that endoscopic therapy for large pedunculated and sessile colorectal polyps is a safe and effective treatment with minimal morbidity and no mortality. We found that despite experienced endoscopists performing colonoscopy it was difficult to predict which polyps are malignant. However large pedunculated polyps seem to carry a significant malignant potential.
Influence of NPM1 and FLT3-ITD Status On Outcome in Relapsed/Refractory AML Patients with Normal Karyotype and Receiving Salvage Therapy Including Gemtuzumab Ozogamicin (GO).
Authors: Patrice Chevallier, Thomas Prebet, Arnaud Pigneux, Mathilde Hunault, Jacques Delaunay, Frederic Perry, Laurence Lode, Steven Richebourg, Odile Blanchet, Norbert Vey, Norbert Ifrah, Noel-Jean Milpied, Didier Blaise, Jean-Luc Harousseau, Mohamad Mohty
Journal: Blood (2009)
Abstract B38: Clinical translation of nuclear export inhibitor in metastatic pancreatic cancer
Authors: Asfar S. Azmi, Irfana Muqbil, Amro Aboukameel, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad, Philip A. Philip
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease in urgent need of newer therapeutic modalities. PDAC tumors are very heterogeneous and carry alterations in many critical pathways rendering the design of therapy against a single pathway unrealistic. The disease requires a broad form of therapy that can target the activation of multiple tumor suppressor proteins (TSPs) simultaneously. We have shown that over-expression of the nuclear exporter protein CRM1 in PDAC leads to functional inactivation of TSPs (such as FOXO3a, p27, Par-4 and p53) through their mislocalization to the cytoplasmic compartment. We clearly demonstrated that targeted inhibition of CRM1 by CRISPR/Cas9 validated Specific Inhibitor of Nuclear Export (SINE) KPT-330/Selinexor can restore the function of multiple TSPs leading to PDAC cell death and tumor inhibition in orthotopic models. More significantly, our findings show that SINE synergize with gemcitabine (GEM) and nab-paclitaxel leading to enhanced PDAC growth inhibition, apoptosis, and spheroid disintegration of PDAC derived cancer stem cells (CSCs) that undergo epithelial-to-mesenchymal transition (EMT). The observed synergy was due in part to enhanced nuclear localization of TSPs and suppression of CSC markers alongside reversal of EMT markers. RNA from quadruplet combination treatment samples were subjected to Agilent HT12 microarrays and differentially expressed genes (p&amp;lt;0.01) were subjected to pathway analysis. Our computational analysis demonstrated reversal of immune suppressive networks and suppression of CSC sustaining networks. Most importantly we observed activation of fibroblast specific cell death pathways highlighting an as of yet unexplored role of CRM1 in sustaining fibroblast growth that is recognized to support high desmoplastic reaction (DR) in PDAC. Our multi-model pre-clinical work has led to the approval of a Phase Ib/II clinical study involving GEM-nab-paclitaxel-Selinexor for metastatic PDAC (NCT02178436). Citation Format: Asfar S. Azmi, Irfana Muqbil, Amro Aboukameel, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad, Philip A. Philip.{Authors}. Clinical translation of nuclear export inhibitor in metastatic pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B38.
Abstract 3922: Novel hepatocyte growth factor and macrophage stimulating protein antagonists for the treatment of castration-resistant prostate cancer
Authors: Brett Vanderwerff, Kevin Church, Leen Kawas, Joseph Harding
Journal: Cancer Research (2015)

Abstract Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer that is refractory to androgen deprivation therapy and characterized by aggressive growth, extensive metastasis formation, and poor prognosis. CRPC is temporarily manageable by the first-line chemotherapeutic docetaxel, but will eventually progress as a chemoresistant cancer, prompting a need for additional therapeutics to either replace docetaxel or to be used in combination therapies that increase the effectiveness of chemotherapy. The aberrant activation of the tyrosine kinase receptor c-Met by the active, dimeric form of hepatocyte growth factor (HGF) and the tyrosine kinase receptor RON by macrophage stimulating protein (MSP) results in the overactivation of signaling pathways that encourage cell proliferation, migration, and survival, contributing to the malignant behavior and chemoresistance of many cancers. The onset of metastatic prostate cancer is associated with both increased serum levels of HGF and expression of c-Met and RON in metastatic growths. Our laboratory has developed small molecules that inhibit HGF dimerization, c-Met activation, and malignant cell behaviors in several cancer cell types. Considering the high degree of homology between HGF and MSP, we predict that our strategy for inhibiting the activation of HGF can be extended to develop compounds that dually inhibit HGF and MSP. We hypothesize that inhibiting HGF and MSP with our antagonists will correspondingly reduce activation of c-Met and RON and suppress tumor growth and metastasis in CRPC. We further anticipate a therapy that combines our antagonists and docetaxel will increase the efficacy of chemotherapy by blunting the pro-survival properties of the HGF/c-Met and MSP/RON systems. Preliminary results indicate that our HGF dimerization antagonist Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] significantly inhibits the migration of CRPC cells and increases their susceptibility to docetaxel treatment in vitro. The primary objective of this study is to investigate the feasibility of HGF, MSP, and HGF/MSP dual antagonists as a therapy for CRPC either alone or in combination with docetaxel. Citation Format: Brett Vanderwerff, Kevin Church, Leen Kawas, Joseph Harding. Novel hepatocyte growth factor and macrophage stimulating protein antagonists for the treatment of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3922. doi:10.1158/1538-7445.AM2015-3922
399. Early Correction of Neuromuscular Deficits in Pompe Disease Is Required for Restoration of Strength Following Gene Therapy
Authors: Adrian G. Todd, Jessica A. McElroy, Robert W. Grange, David D. Fuller, Glenn A. Walter, Barry J. Byrne, Darin J. Falk
Journal: Molecular Therapy (2015)

We have recently reported pathology of the neuromuscular junction (NMJ) in Pompe disease, reflecting disruption of neuronal and muscle homeostasis as a result of glycogen accumulation. The objective of this study was to examine how alterations of the NMJ contribute to Pompe disease pathology. An AAV9 vector encoding GAA (AAV9-hGAA) was injected directly into the tibialis anterior muscle of Gaa-/- mice at early- mid- and severe- pathological time points. Gene expression of NMJ-related genes, in situ muscle force production, clearance of glycogen in conjunction with histological assessment of the NMJ was subsequently performed in all animals. Our data demonstrate that AAV9-hGAA is able to replace GAA to the affected tissue and modify AChR mRNA expression, muscle force production, motor endplate expansion and innervation status of the NMJ. The degree of restoration for these outcomes is limited by progression of neural pathology. Early restoration of GAA activity in muscle and neural cells was most effective, while late correction of GAA expression was not effective in modifying parameters reflecting NMJ structure and function nor in force restoration despite resolution of glycogen storage in muscle. Our data provide new mechanistic insight into the pathology of Pompe disease and suggest that early systemic correction to both neuronal and muscle tissues may be essential for successful correction of neuromuscular function in Pompe disease.
Abstract 303: Effect of scaffold on drug sensitivity of multicellular spheroids: Which method is close to in vivo and suitable for HTS
Authors: Norio Masuda, Atsushi Mizuno, M.Mamunur Rahman, Kazuya Arai, Manabu Itoh
Journal: Cancer Research (2015)

Abstract Background: Three-dimensional (3D) cell culture models are more extensive to be better models than two-dimensional (2D) cell culture models due to enriched cellular signaling pathways, cell to-cell contact, more representative of tissue morphology, and predictive of drug responses in vivo. Different drugs screening and various biological responses between 2D and 3D cell culture models have been reported. However, very little information is available on cell function and/or drug susceptibility caused by a difference in methodology of three dimensional culture. Here, we compared drug responses of various cancer cells against distinctive anti-cancer drugs when grown in monolayer, scaffold 3D culture (Matrigel, NanoCuluture Plate (NCP)) or scaffold-free 3D culture models (ultra-low attachment round bottom plate), and also confirmed which method is suitable for high-throughput screening for robust three-dimensional screening model. Method: We examined drug sensitivities of different lung cancer (A549, H226, H1650), breast cancer (SKBR-3, JIMT1), and prostate cancer (DU145) cell lines under monolayer or 3D cell culture conditions against several anti-cancer agents i.e. molecular targeted agent (Gefitinib, Afatinib, Temsirolimus, Vemurafenib, Vismodegib, Sorafenib), demethylation agent (Azacytidine, Decitabine), anti-microtubule agent (Docetaxel), alkylating agent (Cisplatin, Irinotecan), antimetabolite agent (5-FU, Gemcitabine, Methotrexate). The conditions of these assays are optimized for each culture method. Cell proliferation was measured by ATP assay. Furthermore, we analyzed the biological/ morphological differences among 3D culture methods (scaffold or scaffold-free culture models). Result: Large variations in drug responses were observed among the different cell culture models. Cells grown in 3D scaffold culture model (NCP) were more drug sensitive than other cell culture models. Especially docetaxel, 5-FU, and methotrexate showed clear growth inhibition in three dimensional scaffold culture models (NCP) than scaffold-free culture models (round-bottom). Conclusion: In this study, we showed that scaffold 3D culture is appropriate for anti-cancer drug-susceptibility test. We also proposed that NanoCuluture plate which is 3D scaffold culture model, can be used as a sophisticated high-throughput three-dimensional drug screening model. Citation Format: Norio Masuda, Atsushi Mizuno, M.Mamunur Rahman, Kazuya Arai, Manabu Itoh. Effect of scaffold on drug sensitivity of multicellular spheroids: Which method is close to in vivo and suitable for HTS. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 303. doi:10.1158/1538-7445.AM2015-303
Abstract 3636: Targeting the MLL complex in castration resistant prostate cancer
Authors: Rohit Malik, Amjad P. Khan, Irfan A. Asangani, Marcin Cieślik, John R. Prensner, Xiaoju Wang, Matthew K. Iyer, Xia Jiang, Dmitry Borkin, June Escara-Wilke, Rachell Stender, Yi-Mi Wu, Xuhong Cao, Felix Y. Feng, Jolanta Grembecka, Tomasz Cierpicki, Arul M. Chinnaiyan
Journal: Cancer Research (2015)

Abstract Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration resistant prostate cancer (CRPC). Substantial prior work has focused on targeting AR directly; however, the identification and therapeutic targeting of co-activators of AR signaling remains an underexplored area of potential clinical significance. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via its critical subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits the growth of castration resistant tumors in vivo. Furthermore, we find that menin is up-regulated in castration resistant prostate cancer and high expression correlates with poor overall survival. Taken together, our study identifies the MLL complex as a critical co-activator of AR that can be targeted in advanced prostate cancer. Citation Format: Rohit Malik, Amjad P. Khan, Irfan A. Asangani, Marcin Cieślik, John R. Prensner, Xiaoju Wang, Matthew K. Iyer, Xia Jiang, Dmitry Borkin, June Escara-Wilke, Rachell Stender, Yi-Mi Wu, Xuhong Cao, Felix Y. Feng, Jolanta Grembecka, Tomasz Cierpicki, Arul M. Chinnaiyan. Targeting the MLL complex in castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2015-3636
Impact of Novel M-Component Based Biomarkers On to Progression Free Survival After Treatment in Intact Immunoglobulin Multiple Myeloma.
Authors: Efstathios Koulieris, Dimitrios Maltezas, Nikolaou Eytychia, Vassiliki Bartzis, Tatianna Tzenou, Vassiliki Karali, Pessach Ilias, Katerina Sarris, Stephen Harding, Arthur Bradwell, Theodoros P. Vassilakopoulos, Maria K. Angelopoulou, Nikolitsa Kafasi, Panayiotis Panayiotidis, Marie-Christine Kyrtsonis
Journal: Blood (2012)
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome
Authors: Yuna Kim, Hyeong-Min Lee, Yan Xiong, Noah Sciaky, Samuel W Hulbert, Xinyu Cao, Jeffrey I Everitt, Jian Jin, Bryan L Roth, Yong-hui Jiang
Journal: Nature Medicine (2016)
PWE-068 Common malignancies can be missed during investigation for iron deficiency anaemia
Authors: S Pengelly, M Fabricius, D McMenamin, E Wu, M Metzner, S Lewis, K B Hosie
Journal: Gut (2010)

<h3>Introduction</h3> Between 2000 and 2002, 639 consecutive patients referred to the Iron Deficiency Anaemia (IDA) pathway were prospectively collated on a database. We present a case series of potentially missed malignancies. <h3>Methods</h3> 639 patients presenting to the IDA pathway were prospectively entered onto a database. Initial assessment included OGD and colonic imaging. A 5-year review of outcomes was undertaken using patient medical records and hospital histopathology databases to identify important missed diagnoses. <h3>Results</h3> 126 (20%) patients were initially found to have a GI luminal tumour; 55 (9%) of these being malignant. These comprised 48 colorectal and seven upper GI malignancies. 12 non-GI, or GI non-luminal malignancies were found. Complete medical records were available for 595 (93%) of patients. Of the 584 patients in whom a malignancy was not initially found, 15 (3%) were subsequently found to found to have one. Six were colorectal, meaning 11% of the total 54 colorectal cancers presenting initially had been missed. The most common cause was a falsely negative barium enema. Three were upper GI, meaning a surprisingly high 30% of the total of 10 upper GI malignancies presenting had been missed. The most common cause was falsely reassuring OGD biopsy histology. Five non-luminal or non-GI tumours were subsequently found meaning 29% of the total 17 had been initially missed. When the malignancy was found on initial presentation 43% of the patients survived for 5 years after diagnosis, whereas none of the patients whose diagnosis was delayed survived 5 years, with a median survival of 10.5 months from diagnosis. <h3>Conclusion</h3> This is an effective pathway with a very high yield of tumours: 161 (25%), of which 131 were luminal GI tumours and 30 were non-luminal or non-GI tumours. However the pathway still misses significant numbers of malignancies, with barium enemas more prone than colonoscopy to missing tumours, and upper GI, non-luminal and non-GI tumours being more difficult to find. Missed malignancies had poor survival outcomes. For these reasons a high index of suspicion for malignancy in patients with IDA should be maintained.
Abstract 3108: MicroRNA-200B inhibits arsenic-transformed cell migration by targeting protein kinase Cα signaling pathway
Authors: Zhishan Wang, Brock Humphries, Chengfeng Yang
Journal: Cancer Research (2015)

Abstract Arsenic is one of the most common environmental pollutants and long term exposure to arsenic is associated with increased risk of multiple types of cancer including lung cancer. Despite extensive studies, the mechanism of arsenic carcinogenicity has not been elucidated. MicroRNAs (miRNAs) are a large class of small non-coding RNAs and have been shown to play important roles in many fundamental processes of cancer. MiRNA-200b (miR-200b) is a member of miR-200 family, which contains 5 members. The miR-200 family has been shown to inhibit tumor cell migration; however, the underlying mechanisms are not clearly defined. We recently found that miR-200 expression is depleted in arsenic-transformed human bronchial epithelial cells, which are highly migratory and invasive. To further study the mechanism by which miR-200 inhibits tumor cell migration, we investigated the effects of stably expressing miR-200b on arsenic-transformed cell migration. We found that stably expressing miR-200b drastically inhibits arsenic-transformed cell migration. Wnt5b and protein kinase Cα (PKCα) are highly expressed in arsenic-transformed cells. Stably expressing miR-200b significantly down-regulated protein levels of both Wnt5b and PKCα. Combining bioinformatics screening and 3′UTR luciferase reporter assays, we identified PKCα but not Wnt5b as a new direct target of miR-200b. We also found that siRNA knocking down Wnt5b greatly reduces PKCα activation while inactivating PKCα drastically decreases Wnt5b level, revealing a positive feedback loop between Wnt5b and PKCα. Knocking down Wnt5b or PKCα phenocopy the effect of stably expressing miR-200b on cell migration. Moreover, enforced expression of PKCα impairs the inhibitory effect of miR-200b on cell migration. These findings not only reveal a novel mechanism showing that miR-200b inhibits tumor cell migration by targeting PKCα and Wnt5b-PKCα positive feedback loop, also suggest that deregulation of miR-200b, Wnt5b and PKCα plays an important role in arsenic carcinogenesis. Citation Format: Zhishan Wang, Brock Humphries, Chengfeng Yang. MicroRNA-200B inhibits arsenic-transformed cell migration by targeting protein kinase Cα signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3108. doi:10.1158/1538-7445.AM2015-3108
Testing for antineutrophil cytoplasmic antibodies (ANCAs) in patients with systemic vasculitides and other diseases
Authors: Pavel Novikov, Ilya Smitienko, Nikolay Bulanov, Anastasiia Zykova, Sergey Moiseev
Journal: Annals of the Rheumatic Diseases (2016)

Testing for antineutrophil cytoplasmic antibodies (ANCAs) in patients with