tbuckley/cabot-search huggingface dataset:
564. Finding the Needle in a Haystack: Precise Genome Editing With a Multi-Reporter Selection Systems
Authors: Benjamin L. Oakes, Danny F. Xia, Elizabeth F. Rowland, Jeffrey C. Miller, Edward J. Rebar, Marcus B. Noyes
Journal: Molecular Therapy (2015)

Designer nucleases have revolutionized the study of common model organisms by enabling the simple and efficient manipulation of specified genomic sequences. However, therapeutic application of this technology may be limited by predictable and unanticipated off-target lesions that may be prevalent with all nuclease platforms to lesser and greater extents. This limitation may become even more problematic when desired targets are homologous to other genome sequences. Here we report the development of a multi-reporter selection system for the generation of nucleases that can discriminate between highly homologous targets. We have applied this system to create zinc finger nuclease (ZFNs) that can discriminate between highly homologous sequences from the CCR5 and CCR2 genes. These nucleases were tested in human cell culture and demonstrate strong on-target activity (≈10-60% indel frequency) with minimal or no nuclease activity at CCR2. Further, an unbiased screen of off-target activity demonstrates excellent genome-wide fidelity. In one case, the nuclease pair results in only one off-target with greater than 0.1% indel frequency (0.37%) and an aggregate off-target activity of 0.5%. This system offers a simple approach to generate nucleases, zinc finger or otherwise, with exceptional genome-wide fidelity regardless of target.
Clinical Prognostic Models in Diffuse Large B-Cell Lymphoma Patients Are Still Essential in the Rituximab Era
Authors: Luis Alberto de Padua Covas Lage, Renata Oliveira Costa, Abrahão Elias Hallack Neto, Sheila Siqueira, Rodrigo Santucci, Henrique Moura de Paula, Juliana Pereira
Journal: Blood (2014)
PTU-004 Safe and Effective Day Case Endoscopic Resection of Giant Colorectal Adenomas Greater than 8CM is Achievable in a Tertiary Referral Unit
Authors: A Emmanuel, S Gulati, M Burt, B Hayee, A Haji
Journal: Gut (2016)

<h3>Introduction</h3> There are few reports on the management of very large sessile colorectal polyps in western practice. Endoscopic resection of these lesions can be technically challenging and they have traditionally been subjected to surgical resection in western centres. Our aim was to determine the safety and effectiveness of endoscopic resection of giant colorectal polyps in a tertiary referral interventional endoscopy unit. <h3>Methods</h3> All lesions were assessed with magnification chromoendoscopy. Patients with colorectal polyps greater than or equal to 8 cm deemed suitable for endoscopic resection were included. Several techniques were employed including piecemeal endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and hybrid techniques involving EMR, ESD, transanal resection or transanal endoscopic microsurgery (TEMS). All patients underwent surveillance magnification chromoendoscopy at 3 and 12 months. <h3>Results</h3> 88 lesions greater than or equal to 8 cm were resected with a median size of 10 cm (range 8 cm-16cm). Mean age was 74 years. 49 lesions were in the rectum or rectosigmoid, 13 in the right colon and 27 in the descending and sigmoid colon. There were 6 tubular adenomas, 73 tubulovillous adenomas, 7 adenocarcinomas and 1 sessile serrated adenoma. The recurrence rate was 17%, 64% detected at the first surveillance endoscopy and 36% later recurrences. Of these, 2 patients required surgery in the form of TEMS and a right hemicolectomy, 1 died of unrelated causes, and the rest were managed with a repeat endoscopic resection and were free from recurrence at last surveillance. There were no clinically significant perforations. 3 perforations were closed with endoscopic clips and managed conservatively without complications. There were 2 unplanned admissions for bleeding which did not require further intervention. The recurrence and complication rate were significantly higher than for adenomas smaller than 8 cm. 72% were successfully completed as day cases. Of those patients without invasive cancer at their initial resection and alive at last follow up, 93% avoided surgery and were free from recurrence. <h3>Conclusion</h3> Successful endoscopic resection of giant colorectal adenomas is achievable in a western setting with a low risk of complications. In our series, none of 49 patients with rectal or rectosigmoid lesions, who would have traditionally required an anterior resection or abdominoperineal excision, required a major surgical resection. Almost all patients with benign polyps were successfully treated endoscopically and avoided surgery. Nonetheless, it is associated with a higher risk of complications and recurrence compared with lesions less than 8 cm and therefore should be considered in specialist units. <h3>Disclosure of Interest</h3> None Declared
Abstract LB-063: PTEN function is controlled by recruitment to cytoplasmic vesicles
Authors: Adam Naguib, Gylua Bencze, Hyejin Cho, Wu Zheng, Ante Tocilj, Elad Elkayam, Christopher R Faehnle, Nadia Jaber, Christopher Pratt, Muhan Chen, Wei-Xing Zong, Michael S Marks, Leemor Joshua-Tor, Darryl J Pappin, Lloyd C. Trotman
Journal: Cancer Research (2015)

Abstract PTEN is thought to function at the plasma membrane where receptor tyrosine kinases activate PI 3-Kinases. Yet the majority of PTEN is located throughout the cytoplasm so that only a fraction of PTEN could be actively suppressing PI 3-K signaling at any time. Here we show that cytoplasmic PTEN is distributed along microtubules, tethered to vesicles via interaction with phosphatidylinositol 3- phosphate (PI(3)P), the signature lipid of endosomes. We demonstrate that the C2 domain of PTEN specifically binds PI(3)P via the CBR3-loop. Mutations that render the CBR3-loop incapable of PI(3)P binding abrogate PTEN function in cells but not in vitro. The loss-of-function in cells is rescued by fusion of the canonical PI(3)P vesicle targeting domain, FYVE, to CBR3-loop mutant PTEN, demonstrating the functional relevance of PTEN activity on endosomal membranes. These findings introduce an entirely unexpected site of action of the PTEN tumor suppressor. Furthermore, they introduce the concept of PI 3-K signal activation over the vast surface of the plasma membrane that is contrasted by PTEN-mediated signal termination on the discretely sized and much smaller surfaces of endocytic vesicles. Implications of these results for cancer signaling and growth control will be discussed. Note: This abstract was not presented at the meeting. Citation Format: Adam Naguib, Gylua Bencze, Hyejin Cho, Wu Zheng, Ante Tocilj, Elad Elkayam, Christopher R Faehnle, Nadia Jaber, Christopher Pratt, Muhan Chen, Wei-Xing Zong, Michael S Marks, Leemor Joshua-Tor, Darryl J Pappin, Lloyd C. Trotman. PTEN function is controlled by recruitment to cytoplasmic vesicles. [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 LB-063. doi:10.1158/1538-7445.AM2015-LB-063
Association Between Hospitalization for Infection and Suicide
Authors: Michael Silverman, Lise Bondy
Journal: JAMA Psychiatry (2016)

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Abstract 722: Caveolin-1-dependent endocytosis enhanced chemosensitivity of TDM-1 in HER-2-positive breast cancer cells
Authors: Yuan-Chiang Chung, Wan-Chen Wei, King-Jen Chang, Wei-Ting Chao
Journal: Cancer Research (2015)

Abstract Trastuzumab emtansine (TDM-1, kadcyla) is the antibody drug conjugate (ADC) was approved to treat HER-2 positive metastatic breast cancer. Although its effectiveness, however, the biomarker of drug resistance of TDM-1 has not been identified. The efficacy of ADC is restricted to the antibody internalization in the cell; therefore, the drug sensitivity may be associated with cellular vesicle trafficking system. Caveolin-1, which is the 21 KD membrane protein that is required for caveolae structure formation and membrane endocytic transport. In this study, the relationship of caveolin-1 expression and the chemosensitivity of TDM-1 in HER-2 positive breast cancer cells was investigated. Immunohistochemical staining of 32 specimens of breast cancer patients were evaluated for caveolin-1 expression. For in vitro study, BT-474 and SKBR-3 breast cancer cells which represent different caveolin-1 expression were treated with trastuzumab or T-DM1. Cell viability and molecular localization were examined. Cellular caveolin-1 expression was also manipulated by transfection of GFP tagged caveolin-1 or caveolin-1 shRNA plasmid, cell viability was then determined after drug treatment. In the results, Immunohistochemical study showed 68% (22/32) overexpression of Caveolin-1 in breast cancerous specimens. And eight cases with high expression of Caveolin-1 were found in HER-2 positive breast cancerous patients (72.1%, 8/11). In cell biology study, T-DM1 was found colocalized with caveolin-1 by confocal microscopy. SKBR-3 which represents higher caveolin-1 expression than BT-474 was more sensitive to T-DM1 treatment. After molecular transfection, BT-474 cells with overexpression of caveolin-1 increased chemosensitivity in the treatment of TDM-1, instead, SKBR-3 cells transfected with caveolin-1 shRNA decreased T-DM1 sensitivity. Expression of caveolin-1 could mediate endocytosis and promoting the internalization of TDM-1 into HER-2 positive cancer cells. Thereafter, caveolin-1 may be an effective predictor for TDM-1 treatment in the future. Citation Format: Yuan-Chiang Chung, Wan-Chen Wei, King-Jen Chang, Wei-Ting Chao. Caveolin-1-dependent endocytosis enhanced chemosensitivity of TDM-1 in HER-2-positive breast cancer cells. [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 722. doi:10.1158/1538-7445.AM2015-722
OP28PRELIMINARY RESULTS OF THE PROSPECTIVE FEASIBILITY CNS GCT-4 CONSORTIUM TRIAL FOR PATIENTS WITH REFRACTORY/RECURRENT CNS GERM CELL TUMORS (GCT)
Authors: Jonathan L. Finlay, Kelley Haley, Yin Liu, Diana Osorio, Sharon Gardner, Jeffrey Allen, Girish Dhall
Journal: Neuro-Oncology (2015)

INTRODUCTION: We present updated findings on the response rate, toxicity and early outcomes of a re-induction regimen of gemcitabine, oxaliplatin and paclitaxel (GemPOx) administered, in responsive patients, prior to myeloablative chemotherapy and autologous hematopoietic cell rescue (HDCx + AuHCR). METHOD: Since December 2004, 14 recurrent or refractory patients (12 MMGCT, 2 germinoma; 12 males; mean age 16.5 years, range 7-34 years) have been treated with up to 4 cycles of gemcitabine (800mg/m2), oxaliplatin (100mg/m2) and paclitaxel (170 mg/m2), administered on one day at 14 days intervals. RESULTS: Of 14 patients, five were treated on a preceding feasibility pilot with 1-3 cycles of GemPOx, and nine have been formally enrolled on an ongoing prospective multi-center trial. Seven patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions and two developed progressive disease (PD) while on GemPOx. Twelve of the 14 patents subsequently underwent HDCx + AuHCR; 6 subsequently received irradiation. Transient hepatotoxicity and pancytopenia were the most prevalent toxicities. Five patients continue alive and disease-free for 9 + , 20 + , 22 + , 26+ and 28+ months since end of therapy. CONCLUSION: GemPOx appears to be an effective re-induction regimen for patients with recurrent CNS MMGCT, with acceptable toxicities. The ongoing multi-center, international trial should confirm this and demonstrate the contribution of GemPOx towards improved survival when followed by HDCx + AuHCR with or without further irradiation, in the setting of minimal residual disease.
Bendamustine Plus Rituximab Versus CHOP Plus Rituximab in the First-Line Treatment of Patients with Indolent and Mantle Cell Lymphomas - First Interim Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany).
Authors: Mathias J. Rummel, U. von Gruenhagen, N. Niederle, F. Rothmann, H. Ballo, E. Weidmann, M. Welslau, G. Heil, H. Duerk, M. Stauch, C. Losem, A. Matzdorff, C. Balser, K. Schalk, D. Kofahl-Krause, U. Kaiser, W. Knauf, A. Banat, D. Hoelzer, W. Brugger
Journal: Blood (2007)
The Outcome of Relapsed Childhood Core Binding Factor Acute Myeloid Leukemia: A Report from the JPLSG AML-05R Study
Authors: Hiroshi Moritake, Shiro Tanaka, Hideki Nakayama, Takako Miyamura, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Akiko M. Saito, Norio Shiba, Yasuhide Hayashi, Daisuke Tomizawa, Takashi Taga, Hiroaki Goto, Atsushi Manabe, Keizo Horibe, Shuki Mizutani, Souichi Adachi
Journal: Blood (2015)
Abstract LB-248: Protein arginine methyltransferase 5 (PRMT5) inhibition as a therapeutic strategy in B-cell lymphoma
Authors: Olena Barbash, Sarah Gerhart, David Soong, Christine Thompson, Rocio Montes de Oca, Ping Zhang, Charles McHugh, Kristy Kuplast, Christina Majer, Richard Chesworth, Jesse Smith, Robert Copeland, Elayne Penebre, Kenneth Duncan, Neil Johnson, Chris Carpenter, Ryan Kruger
Journal: Cancer Research (2015)

Abstract PRMT5 is responsible for symmetric dimethylation of arginine residues in glycine and arginine rich (GAR) motifs on a variety of cytosolic and nuclear proteins including histones, spliceosome components, regulators of translation, transcription factors, kinases and others. PRMT5 driven methylation of some of these proteins has been implicated in tumorigenesis. For example, PRMT5 deposits repressive marks on histones and silences a subset of tumor suppressor genes, such as RB and ST7. PRMT5 methylation of non-histone substrates (such as E2F1 and p53) also contributes to cancer cell growth and death. PRMT5 driven methylation of spliceosome subunits and components of translational machinery has been well described but its connection to PRMT5's role in cancer has not been established. We have identified first-in-class small molecules that are highly potent, selective, reversible inhibitors of PRMT5. Cellular mechanistic studies revealed that PRMT5 inhibition decreases symmetric arginine dimethylation on a variety of cellular proteins including spliceosome components, histones and transcription factors. PRMT5 inhibition leads to gene expression and splicing changes ultimately resulting in the induction of p53 in lymphoma cell lines. In addition to impacting the p53 pathway, PRMT5 inhibition leads to attenuation of the expression of cell cycle related genes, genes involved in ribosome and spliceosome homeostasis, as well as genes important for cellular metabolism. PRMT5 inhibitor attenuates proliferation and induces cell death in a subset of mantle cell and diffuse large B-cell lymphoma cell lines and inhibits tumor growth in xenograft models of mantle cell lymphoma. These data underline the potential of PRMT5 inhibitors as a therapeutic strategy in mantle cell and diffuse large B-cell lymphoma. Citation Format: Olena Barbash, Sarah Gerhart, David Soong, Christine Thompson, Rocio Montes de Oca, Ping Zhang, Charles McHugh, Kristy Kuplast, Christina Majer, Richard Chesworth, Jesse Smith, Robert Copeland, Elayne Penebre, Kenneth Duncan, Neil Johnson, Chris Carpenter, Ryan Kruger. Protein arginine methyltransferase 5 (PRMT5) inhibition as a therapeutic strategy in B-cell lymphoma. [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 LB-248. doi:10.1158/1538-7445.AM2015-LB-248
PTU-085 Rigid sigmoidoscopy: widely used but poorly taught. A survey of UK surgical and medical gastroenterology trainees
Authors: A D Dhanda, P Marden
Journal: Gut (2010)

<h3>Introduction</h3> Rigid sigmoidoscopy is an invasive lower gastrointestinal investigation. It requires good communication and procedural skills and knowledge of relevant anatomy and pathology. However, there is no formal structure for training and assessment of this procedure in England and Wales. There are advocates for phasing it out in favour of better access to flexible sigmoidoscopy especially in view of reduced waiting times for this procedure. However rigid sigmoidoscopy is still frequently performed in outpatient and inpatient settings and therefore as with all clinical procedures training requirements should be standardised nationally. <h3>Methods</h3> This study aims to assess gastroenterology and general surgery trainees9 experience and training in the use of rigid sigmoidoscopy. An Internet survey was distributed via the Regional Training Programme Directors for all gastroenterology trainees in England and Wales and all general surgery trainees in England. <h3>Results</h3> There were 74 responses. 46% were gastroenterology trainees and 54% were surgical trainees (of these 35% were colorectal surgery trainees). There was an even representation of different stages in training: ST3 19%, ST4 24%, Year 3 16%, Year 4 15%, Year 5 9% and Out of Programme 16%. 46% of trainees had performed &gt;100 rigid sigmoidoscopies and only 12% &lt;10. 62% had been supervised in performing 1 to 5 procedures but 18% had never been supervised. 85% took verbal and 4% written consent but 62% did not inform patients about the risk of haemorrhage and perforation. No trainee surveyed had ever attended a formal training course and 88% had never had either a formative or summative Direct Observation of Procedural Skills (DOPS) assessment. Despite this, 55% of trainees felt that their training was adequate and 5% that it was excellent. 40% felt that training was either insufficient or non-existent. For future trainees 53% did not feel any formal training was necessary, 35% thought that formative and summative DOPS assessments would be beneficial and 7% wanted a training course with a further 4% wanting both a training course and DOPS assessments. <h3>Conclusion</h3> Rigid sigmoidoscopy is a widely used procedural skill among general surgery and gastroenterology trainees. This survey highlights some worrying facts: a large proportion of current trainees were never supervised when first learning the procedure and although the majority take some form of consent, 62% do not inform the patients of the relevant risks of the procedure. While the response rate was disappointing (5.6%), this study clearly suggests a need for structured training and assessment in rigid sigmoidoscopy and improved availability of training courses throughout England and Wales.
Hodgkin Lymphoma In First Remission: Routine PET/CT Imaging Is Not Superior To Clinical Follow-Up For Patients Without Residual Mass: Results Of a Bi-National Study Including 368 Patients
Authors: Leanne Berkahn, Frcpa, Tatiana Mashiach, Michael Frumer, Ariel Agur, Bridgett McDiarmid, Rachel Bar-Shalom, Ora B. Paltiel, Neta Goldschmidt
Journal: Blood (2013)
Abstract 4621: Validation and calibration of next-generation sequencing to identify Epstein-Barr Virus-positive gastric cancer
Authors: M. Constanza Camargo, Reanne Bowlby, Andy Chu, Chandra S. Pedamallu, Vesteinn Thorsson, Sandra Elmore, Andrew Mungall, Adam Bass, Margaret L. Gulley, Charles S. Rabkin
Journal: Cancer Research (2015)

Abstract Background: Gastric adenocarcinoma was recently classified by a large genomic study into four molecular subtypes, including one defined by Epstein-Barr virus (EBV)-positivity. EBV infection in tumors is conventionally assessed by in situ hybridization (ISH), but detection of viral nucleic acids by next-generation sequencing represents a potential alternative. Methods: Normalized EBV read counts were determined by whole genome, whole exome, mRNA and miRNA sequencing for 295 fresh-frozen gastric tumor samples. Formalin-fixed, paraffin-embedded tissue sections were retrieved for ISH confirmation of 13 high-EBV and 11 low-EBV cases selected at random. Results: By each sequencing method, numbers of EBV reads were bimodally distributed across tumors, with a minority having much higher counts. In pairwise comparisons, individual samples were either consistently high or consistently low by all genomic methods for which data were available. Empiric cut-offs based on molecular data of 1000 normalized reads for whole genome, 100 for exome, 4 for mRNA and 5000 for miRNA had perfect concordance identifying 26 (9%) tumors as EBV-positive. One sample tested by ISH lacked tumor cells. For the 23 tumors with EBV status determined by both approaches, EBV-positivity or -negativity by molecular testing was confirmed by EBER-ISH in all but one case (kappa = 0.91). The exception was a microsatellite instability-type cancer EBV-negative by both mRNA and miRNA sequencing, with equivocally positive ISH interpretation. Conclusions: EBV-positive gastric tumors may be accurately identified by quantifying viral sequences in genomic data. Simultaneous analyses of human and viral DNA, mRNA and miRNA could streamline tumor profiling for clinical care and research. Citation Format: M. Constanza Camargo, Reanne Bowlby, Andy Chu, Chandra S. Pedamallu, Vesteinn Thorsson, Sandra Elmore, Andrew Mungall, Adam Bass, Margaret L. Gulley, Charles S. Rabkin. Validation and calibration of next-generation sequencing to identify Epstein-Barr Virus-positive gastric 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 4621. doi:10.1158/1538-7445.AM2015-4621
Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers
Authors: Richard M. England, Jennifer I. Hare, Jennifer Barnes, Joanne Wilson, Aaron Smith, Nicole Strittmatter, Paul D. Kemmitt, Michael J. Waring, Simon T. Barry, Cameron Alexander, Marianne B. Ashford
Journal: Journal of Controlled Release (2016)
Phase II Study of Vorinostat in Combination with Idarubicin (Ida) and Cytarabine (ara-C) as Front Line Therapy in Acute Myelogenous Leukemia (AML) or Higher Risk Myelodysplastic Syndrome (MDS).
Authors: Guillermo Garcia-Manero, Francesco Paolo Tambaro, B. Nebiyou Bekele, Elias Jabbour, Farhad Ravandi, Hui Yang, Gautam Borthakur, Tapan Kadia, Jorge Cortes, Stefan Faderl, Marina Konopleva, Sherry Pierce, Jan A. Burger, Zeev Estrov, Susan O'Brien, Deborah Thomas, Willie Newsome, Hagop Kantarjian
Journal: Blood (2009)
OP40CONTROL OF MIGRATION IN NORMAL AND GLIOMA NEURAL STEM CELLS BY THE STEM CELL FACTOR PROMYELOCYTIC LEUKAEMIA PROTEIN (PML)
Authors: D.A.V. Amodeo, J. Henderson, S. Bartesaghi, M. Vouri, R. Roshani, S. Oberndorfer, M. Shaked-Rabi, D. Dinsdale, P. Nicotera, C. Jones, D. Michod, S. Brandner, P. Salomoni
Journal: Neuro-Oncology (2015)