tbuckley/cabot-search huggingface dataset:
563. Rapid and Nuclease-Free Generation of Gene-Repaired Human iPS Cells from IL2RG-Defective Fibroblasts
Authors: Ko Mitani, Naoyuki Ohta, Nozomu Nihashi, Yuzuru Iweanaga, Manami Ohtaka, Ken Nishimura, Mahito Nakanishi
Journal: Molecular Therapy (2015)

Recent developments of artificial nucleases, such as TALENs and CRISPR/Cas9, have made gene repair therapy of inherited diseases more realistic. However, off-target chromosomal breaks resulting in imprecise DNA repair by the nucleases are still significant concerns from safety aspects, which is the most critical issue of clinical gene therapy. Furthermore, prolonged culture during induction and manipulation of induced pluripotent stem cells (iPSCs) has been shown to increase point mutations and copy number variations in the iPSC genome, raising additional safety concerns for therapeutic applications of iPSCs. In order to minimize cell culture for iPSC induction and achieve efficient gene repair without using nucleases, we examined a strategy of consecutive iPSC induction and gene repair without cell cloning between the two processes. For this purpose, we utilized Sendai virus vector (SeV)-mediated iPSC induction and helper-dependent adenoviral vector (HDAdV)-mediated gene targeting. To mimic somatic cells from patients of X-linked severe combined immunodeficiency, we firstly knocked out exon 1 of the common gamma chain of human interleukin-2 receptor (IL2RG) locus by utilizing TALENs, and subsequently derived fibroblast-like cells. Next, these cells were subject to iPSC induction by using the SeV expressing Yamanaka factors, SeVdp(KOSM). Instead of isolating and characterizing individual SeV-iPS colonies before gene targeting, iPSC-like colonies were grown as a cell population. Twenty-two to 26 days after SeV infection, the cells were transduced with a HDAdV targeting the IL2RG locus. This HDAdV was designed to introduce the PGK-neo cassette into intron 4 and to repair the mutation of exon 1. Cells were subject to G418/FIAU selection to isolate gene-targeted SeV-iPS colonies. Correct targeting at the IL2RG locus by the vector in G418/FIAU double-resistant colonies was verified by PCR analyses. From two independent experiments, the gene targeting frequencies were similar to those in authentic human iPSCs at 1.6 – 1.8 × 10-5 per cell and 60 – 75% of chromosomal integration (G418/FIAU-resistance), among them 60 – 80% of gene-targeted colonies had the exon 1 mutation repaired. At the time of HDAdV infection, the SeV-iPSCs already showed characteristics of pluripotency, revealed by bisulfite sequencing of the NANOG locus and TRA-1-60 immunostaining. The pluripotency was also maintained in gene-targeted iPSC colonies. From the start of iPSC induction (infection with SeV) to isolation of gene-repaired iPSC colonies, it took only 40 days. We are currently analyzing the expression of IL2RG in differentiated T cells derived from the gene-repaired iPSCs. These results suggest that, by combining efficient methods for iPSC induction and gene targeting, gene repair therapy using patients' somatic cells becomes more realistic.
Randomized Comparison of Cladribine Containing Regimens and COP in Previously Untreated Patients with Small Lymphocytic, Marginal Zone and Follicular Lymphoma.
Authors: Ewa Kalinka, Jaroslaw Wajs, Kazimierz Sulek, Tadeusz Robak, Maria Blasinska-Morawiec, Joanna Sawczuk-Chabin, Bernadetta Ceglarek, Lech Konopka, Piotr Centkowski, Ilona Seferynska, Krzysztof Warzocha
Journal: Blood (2005)
Bone Metabolism and Endocrine Function in Children with Chronic Myeloid Leukemia (CML) Treated with Imatinib during Puberty.
Authors: Fiorina Giona, Stefania Mariani, Annalisa De Vellis, Maria Luisa Moleti, Anna Maria Testi, Mariella D’Angiò, Bruna De Masi, Robert Foa, Lucio Gnessi
Journal: Blood (2007)
Abstract 2601: A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer in vitro and in vivo
Authors: Do Young Lim, Seung Ho Shin, Margarita Malakhova, Mee-Hyun Lee, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2015)

Abstract For decades, lung cancer has been a leading cause of death in the U.S., mainly due to oncogenic signaling pathways activated by carcinogens such as smoking. Various carcinogens induce EGFR/RAS/MAPK signaling that is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 against lung carcinogenesis will be beneficial to these patients. Herein, we examined the therapeutic effects of catechol (also known as pyrocatechol or 1,2-dihydroxybenzene), a naturally occurring chemical in many foods such as apple, banana, apricot, grape, plum, avocado and mushroom. Co-crystallography results suggested that ERK2 is a direct target of catechol. In agreement with the co-crystallography result, catechol was confirmed to inhibit ERK2 kinase activity in vitro. Catechol inhibited anchorage-independent KP2 and H460 lung cancer cell growth in a dose-dependent manner. Phosphorylation of c-Myc, a substrate of ERK2, was reduced in catechol-treated lung cancer cells compared to untreated controls. Decreased c-Myc phosphorylation resulted in its reduced protein stability and subsequent down-regulation of total c-Myc levels. Treatment with catechol induced G1 cell cycle arrest and resulted in a decrease of G1 phase related proteins, CDK2 and cyclin D1. In vivo study results also revealed that catechol inhibited growth of KP2 and H460 xenograft tumors. Phosphorylation levels of c-Myc were also strongly decreased by catechol treatment in vivo. Taken together, we have shown that catechol exerts inhibitory effects on the ERK2/c-Myc signaling axis in lung cancer cells to reduce tumor growth in vitro and in vivo. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis. Citation Format: Do Young Lim, Seung Ho Shin, Margarita Malakhova, Mee-Hyun Lee, Ann M. Bode, Zigang Dong. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer in vitro and in vivo. [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 2601. doi:10.1158/1538-7445.AM2015-2601
Abstract 2393: PDAC cells release BAG3 that activates a paracrine loop with stromal macrophages
Authors: Alessandra Rosati, Anna Basile, Raffaella D'Auria, Morena d'Avenia, Margot De Marco, Antonia Falco, Michelina Festa, Luana Guerriero, Vittoria Iorio, Maria Pascale, Renato Franco, Claudio Arra, Antonio Barbieri, Domenica Rea, Giulio Menichini, Michael Hahne, Marteen Bijlsma, Daniela Barcaroli, David A. Tuveson, Jelena Todoric, Michael Karin, Vincenzo De Laurenzi, Maria Caterina Turco
Journal: Cancer Research (2015)

Abstract Interactions between cancer cells and stromal cells are critically involved in tumor formation, progression and development of metastasis. Here we report for the first time that human pancreatic adenocarcinoma (PDAC) cells secrete BAG3 that binds and activates macrophages, inducing their activation and the secretion of pancreatic cancer- supporting factors. We also identify IFITM-2 as a BAG3 receptor, by its co-precipitation with BAG3 from macrophage cell membrane and by impairment of BAG3- induced activation in IFITM-2- silenced macrophages. Finally we show the importance of this pathway in vivo since in nu/nu mice carrying orthotopic xenografts of human PDAC (MIA PaCa-2) cells, BAG3 sequestration by an anti-BAG3 antibody results in reduced tumor growth and prevents metastastasis formation. In conclusion we have identified a novel paracrine loop involved in PDAC growth and metastatic spreading and shown that its pharmacological blockage with an anti-BAG3 antibody has therapeutic potential. Citation Format: Alessandra Rosati, Anna Basile, Raffaella D'Auria, Morena d'Avenia, Margot De Marco, Antonia Falco, Michelina Festa, Luana Guerriero, Vittoria Iorio, Maria Pascale, Renato Franco, Claudio Arra, Antonio Barbieri, Domenica Rea, Giulio Menichini, Michael Hahne, Marteen Bijlsma, Daniela Barcaroli, David A. Tuveson, Jelena Todoric, Michael Karin, Vincenzo De Laurenzi, Maria Caterina Turco. PDAC cells release BAG3 that activates a paracrine loop with stromal macrophages. [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 2393. doi:10.1158/1538-7445.AM2015-2393
A double-blind, placebo-controlled, phase-II clinical trial to evaluate oral simvastatin as a treatment for vitiligo
Authors: Stefan G. Vanderweil, Shinya Amano, Wei-Che Ko, Jillian M. Richmond, Michelle Kelley, Maryanne Makredes Senna, Andrea Pearson, Sandhya Chowdary, Celia Hartigan, Bruce Barton, John E. Harris
Journal: Journal of the American Academy of Dermatology (2016)
Correlation Between Histological Analysis and Clinical Features of Patients with Suspected Lower Gastro-Intestinal (GI) Graft Versus Host Disease (GVHD): Results of a Single Center Retrospective Study
Authors: Claire Breal, Catherine Mohr, Fanny Sauvestre, Marion Marty, Jean-francois Goussot, Genevieve Belleannee, Reza Tabrizi, Stephane Vigouroux, Noel Milpied
Journal: Blood (2015)
Abstract 1190: Prognostic significance of serine synthesis pathway-related protein expression in patients with resected colon cancer
Authors: Byung Woog Kang, Jong Gwang Kim, Yee Soo Chae, Soo Jung Lee, Shinkyo Yoon, Ghil Suk Yoon
Journal: Cancer Research (2015)

Abstract Background We analyzed the prognostic impact of serine synthesis pathway-related protein expression in a large number of patients with colon cancer. Methods PDK1, PDK2, PKM2, PHGDH, PSAT, and ER betta expression were investigated on the basis of the immunohistochemistry of tissue microarray specimens from 486 colon cancer patients who underwent curative surgery between 2006 and 2010. We scored the staining intensity (0 through 3) and percentage of positive cells (0 through 4), and the staining score was defined as sum of these scores used to categorize the each expression as low (0 through 3) or high (4 or more). Results For the 486 patients, the median age was 66 (30-90) years at the time of surgery. The pathologic stages after the surgical resection were as follows: stage I (n = 98), stage II (n = 213), and stage III (n = 175). A total of 201 (41.4%) was identified as high PDK2 (staining score ≥4). The survival analysis showed that the expression of serine synthesis pathway-related protein had no effect on the overall survival and disease-free survival (DFS) except that the grade of PDK2 expression was significantly associated with the DFS (p = 0.028). On the multivariate analysis that included age, histology, TNM stage, and CEA level, no significant association between the grade of the PDK2 expression and DFS was observed. Conclusion The current study suggests that the tissue expression of serine synthesis pathway-related protein is not an independent prognostic marker for patients with surgically resected colon cancer. Note: This abstract was not presented at the meeting. Citation Format: Byung Woog Kang, Jong Gwang Kim, Yee Soo Chae, Soo Jung Lee, Shinkyo Yoon, Ghil Suk Yoon. Prognostic significance of serine synthesis pathway-related protein expression in patients with resected colon 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 1190. doi:10.1158/1538-7445.AM2015-1190
Drug Development Pipeline for Myeloproliferative Neoplasms: Potential Future Impact on Guidelines and Management
Authors: Prithviraj Bose, Srdan Verstovsek
Journal: Journal of the National Comprehensive Cancer Network (2016)

The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of “clinical improvement” in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations.
Autoantibody-Negative Autoimmune Hepatitis Occurs More Commonly in Patients With Severe Autoimmune Hepatitis
Authors: Nikhil Sonthalia, Samit Jain, Ashok Mohite, Vinay Zanwar, Sunil Pawar, Ravindra Surude, Pravin Rathi
Journal: Clinical Gastroenterology and Hepatology (2016)
Abstract 4337: Comprehensive analysis of genetic variations of genes involved in DNA damage response pathways or cell cycle checkpoints and treatment outcome in non-small cell lung cancer patients treated with platinum doublets
Authors: Jeong Seon Ryu, Bo-Rim Yi, Seul-Ki Lee, Soon-Sun Hong
Journal: Cancer Research (2015)

Abstract Genes involved in DNA damage response (DDR) pathways or cell cycles checkpoints (CCC) are thought to be closely related to effect of platinum doublets, backbone in treatment for lung cancer patients. We tried to evaluate validity of germ-line variations of all genes related to DDR or CCC as potential predictive biomarker of treatment outcome in non-small-cell lung cancer (NSCLC) patients treated with platinum doublets. A total of 967 NSCLC patients treated with platinum doublets as front line chemotherapy was enrolled and divided randomly into three sets: screening, training and validation. For screening set, whole exons, -1,000 bps upstreams, and splicing junctions in the 170 genes related to DDR or CCC were analyzed using next generation sequencing, then genetic variations were selected with several criterions such as minor allele frequency &amp;gt; 5%, call rate &amp;gt; 90%, p value for HWE &amp;gt; 0.001, and impact of genetic variation. Their effects on progression free survival or response to platinum doublets were evaluated in two phases: training and validation process. Clinical characteristics were not different between training (n = 372) and validation (n = 381) cohorts. A total of 4,697 genetic variations and 7 In/Del were identified in screening set, then 232 genetic variations and 7 In/Del from 118 genes were finally selected with predefined criterions. In training cohort, 29 genetic variations were found to be associated with progression free survival or response. However, the effects of these genetic variations were not failed to be validated. In subgroup analysis with non-adenocarcinoma patients, CLSPN (rs79083467), MSH3 (rs32952), and RAD51C (rs12946397) were shown to be associated with progression free survival of the patients (cox p values for CLSPN, MSH3, RAD51C: 0.028, 0.022, 0.035 in training cohort; 0.046, 0.026, 0.008, respectively in validation cohort). In this study, we have failed to show validity of the germ-line variations in predicting treatment outcome of NSCLC patients treated with platinum doublets. This result show germ-line variations related to pharmacodynamics have a limited value in predicting platinum effect. Note: This abstract was not presented at the meeting. Citation Format: Jeong Seon Ryu, Bo-Rim Yi, Seul-Ki Lee, Soon-Sun Hong. Comprehensive analysis of genetic variations of genes involved in DNA damage response pathways or cell cycle checkpoints and treatment outcome in non-small cell lung cancer patients treated with platinum doublets. [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 4337. doi:10.1158/1538-7445.AM2015-4337
PWE-078 Magnification Endoscopy with I-Scan Imaging and Acetic Acid Chromoendoscopy in Barrett’s Oesophagus Improves Neoplasia Detection
Authors: G Lipman, R Bisschops, J Ortiz-Fernández-Sordo, R Sweis, JM Esteban, LB Lovat, K Ragunath, R Haidry
Journal: Gut (2016)

<h3>Introduction</h3> Barrett’s oesophagus (BE) is the pre-cursor for oesophageal adenocarcinoma. Endoscopic surveillance is performed in BE patients to detect dysplasia as an early treatment target. Current surveillance relies on random quadrantic biopsies every 1–2 cm through the BE with targeted biopsies for areas of suspicion. This strategy samples less than 5% of the BE mucosa. We present a novel endoscopic classification system utilising magnification chromo-endoscopy with <i>i-Scan</i> (PENTAX HOYA, Japan) image enhancement technology and acetic acid to improve dysplasia recognition in BE. <h3>Methods</h3> High definition (HD) video recordings of suspicious lesions were collected from patients with non-dysplastic (ND-BE) and dysplastic (D-BE) BE undergoing endoscopy at a high volume tertiary centre. Lesions were recorded with magnification endoscopy in all <i>i-Scan</i> modes both before and after application of 2% acetic acid (ACA) before sampling with biopsy forceps or endoscopic mucosal resection to confirm the histological diagnosis. Six expert endoscopists scored videos using a previously validated mucosal (M) and vascular (V) classification system. Normal mucosa was defined as regular circular or villous pits (M1) and abnormal mucosa defined as distorted or irregular pits or featureless mucosa (M2). Normal vascular pattern was defined as regular and uniform vessels (V1) and abnormal vascular pattern was defined as irregular, dilated corkscrew vessels (V2). Dysplasia was classified if the lesion was felt to be either M2 or V2. <h3>Results</h3> 63 lesions (36 D-BE, 27 ND-BE) were recorded (30 before ACA and 33 after ACA) for analysis. Experts’ average accuracy for dysplasia prediction was 67.8% pre ACA and 75.9% after ACA (p = 0.01). ACA improved the sensitivity of our novel classification system for neoplasia detection from 81% to 88% (p = 0.04). Interobserver Kappa values were 0.253 pre ACA and 0.369 after ACA. <h3>Conclusion</h3> Experts can diagnose D-BE in up to three-quarters of cases using i-Scan magnification endoscopy with acetic acid. ACA improves the sensitivity of diagnosing D-BE. The novel classification system for BE neoplasia has fair agreement between expert endoscopists. <h3>Disclosure of Interest</h3> None Declared
Negative Control Outcomes
Authors: Benjamin F. Arnold, Ayse Ercumen
Journal: JAMA (2016)

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Abstract LB-170: Single cell sequencing identifies clonal stasis and punctuated copy number evolution in triple-negative breast cancer patients
Authors: Ruli Gao, Alexander Davis, Emi Sei, Xiuqing Shi, Anna Unruh, Jill Waters, Amy (Hong) Zhang, Funda Meric-Bernstam, Nicholas Navin
Journal: Cancer Research (2015)

Abstract Intratumor heterogeneity is widely reported in many human tumors including breast cancer. However most studies to date have been limited to genomic analysis of bulk tumor tissues and cytogenetic analysis. Here, we applied single cell copy number profiling to delineate the clonal substructure of triple-negative (ER-, PR-, Her2-) breast cancer (TNBC). We applied Single Nucleus Sequencing (SNS) to profile genomic copy number in 1000 single cells from 11 TNBC patients. Our data show that copy number profiles within the tumor are highly stable, belonging to a few (N = 1-3) major clonal subpopulations that share similar amplifications and deletions,. In addition to the clonal cells, we also identified diverse copy number profiles that belong to two classifications: 1) replicating cells, or 2) apoptotic cells. We also find evidence of rare diploid cells that harbor non-clonal amplification and deletions and may play an important role in aneuploidy initiation. Our data suggests a model of punctuated genome evolution and clonal stasis, in which aneuploidy occurs early in tumor evolution, followed by one or more stable clonal expansion to form the tumor mass. These data challenge the paradigm of gradual copy number evolution and extensive copy number diversity in triple-negative breast cancer, and suggest that that amplifications and deletions are ideal markers for personalized cancer therapy. Citation Format: Ruli Gao, Alexander Davis, Emi Sei, Xiuqing Shi, Anna Unruh, Jill Waters, Amy (Hong) Zhang, Funda Meric-Bernstam, Nicholas Navin. Single cell sequencing identifies clonal stasis and punctuated copy number evolution in triple-negative breast cancer patients. [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-170. doi:10.1158/1538-7445.AM2015-LB-170