tbuckley/cabot-search huggingface dataset:
559. Induction of Fetal Hemoglobin in Adult Erythroblasts by Genome Editing of the Beta-Globin Locus
Authors: Chiara Antoniani, Annalisa Lattanzi, Giulia Pavani, Vasco Meneghini, Elisa Magrin, Leslie Weber, Matthew Porteus, Marina Cavazzana, Fulvio Mavilio, Annarita Miccio
Journal: Molecular Therapy (2016)

Sickle cell disease (SCD) and β-thalassemia are severe anemias characterized by abnormal or reduced production of hemoglobin β-chains. Autologous transplantation of genetically corrected hematopoietic stem cells (HSC) is an attractive therapeutic alternative for patients lacking a compatible HSC donor. Naturally occurring, large deletions in the β-globin locus result in increased fetal hemoglobin (HbF) expression (HPFH, Hereditary Persistence of Fetal Hemoglobin), a condition that mitigates the clinical severity of β-hemoglobinopathies. Here, we integrated BCL11A and GATA1 transcription factor binding site analysis and HPFH mutational data to identify potential HbF silencers in the β-globin locus. Based on this analysis, we designed a CRISPR/Cas9 strategy to disrupt a 13-kb genomic region commonly deleted in HPFH, which includes the Δ- and β-globin genes and putative intergenic HbF silencers, and achieved efficient targeted deletion in erythroid cell lines by plasmid, RNA and lentiviral delivery of the CRISPR/Cas9 nuclease system. RT-PCR showed a dramatic increase in γ-globin mRNA levels in modified adult hematopoietic stem progenitor cells (HSPC)-derived erythroid cell lines (HUDEP-2). FACS and HPLC analysis demonstrated reactivation of HbF and a concomitant decrease in HbA expression. Cell morphology, erythroid marker profile, total Hb levels and erythroid maturation were unaffected, consistent with the asymptomatic phenotype of adult HPFH carriers. The same strategy was tested in primary human erythroblasts by lentiviral transduction of adult CD34+ HSPCs followed by in vitro erythroid differentiation in liquid and clonogenic cultures. Deletion of potential HbF silencers resulted in a 35% increase in γ-globin expression compared to basal levels in primary human erythroblasts as measured by HPLC, suggesting that these sequences could serve as targets for therapeutic genome editing for HbF induction in β-hemoglobinopathies. We are currently testing the efficiency of our CRISPR/Cas9-based strategy in patient-derived HSPCs. Overall, this study contributes to the knowledge of the mechanisms underlying fetal to adult Hb switching, and provides clues for a therapeutic strategy for SCD and β-thalassemia.
Efficacy and Safety of Ponatinib According to Prior Approved Tyrosine Kinase Inhibitor (TKI) Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CP-CML): Results From the PACE Trial
Authors: Dong-Wook Kim, Jorge E. Cortes, Javier Pinilla-Ibarz, Philipp le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane Apperley, H. Jean Khoury, Moshe Talpaz, John F. DiPersio, Daniel DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C Muller, Carlo Gambacorti-Passerini, Stephane Wong, Stephanie Lustgarten, Victor M. Rivera, Tim Clackson, Christopher D. Turner, Frank G Haluska, Francois Guilhot, Michael W. Deininger, Andreas Hochhaus, Timothy P. Hughes, John M Goldman, Neil Shah, Hagop M. Kantarjian
Journal: Blood (2012)
Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study
Authors: Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A. Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew Mungall, Richard Moore, Ryan D. Morin, Nathalie A. Johnson, Laurie H. Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M. Connors, David W. Scott, Christian Steidl, Marco A. Marra, Randy D. Gascoyne, Sohrab P. Shah
Journal: PLoS Medicine (2016)

Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
Electrocardiographic findings in experimental murine myocarditis. Arrhythmias in the chronic stage.
Authors: Chiharu Kishimoto, Akira Matsumori, Chuichi Kawai
Journal: Circulation (1983)

We studied serial electrocardiographic changes in murine myocarditis due to encephalomyocarditis (EMC) virus. After taking control electrocardiograms using standard extremity and 2 precordial leads, 86 mice were intraperitoneally inoculated with a 0.1 ml of the M variant of EMC virus suspension containing 100 TCID50. Electrocardiograms were recorded everyday from the 2nd to the 14th day, and thereafter once every 3-5 days until the 35th day. The cumulative incidence of myocarditis was 90% (77 out of 86). The control electrocardiogram showed a heart rate of 528 ± 87 beats/min (mean ± SD) and PR intervals of 0.03-0.05 sec, and significant rhythm or conduction disturbances were not found. Various electrocardiographic abnormalities, such as atrial (10%) and ventricular (21%) premature contractions, were noticed on the 4th to the 14th day. After 15-35 days arrhythmias still remained in 3 mice. The presence of arrhythmias in the chronic stage of myocarditis suggests that arrhythmias in some patients with no other clinical manifestations may be a sequela of the previous viral myocarditis. Thus, this study may contribute clinically to the clarification of the electrocardiographic characteristics in viral myocarditis.
Abstract 3010: Meiotic cohesin REC8 associates with chromosome instability in melanoma
Authors: Julia Escandon, Scott Lindsey, Mark S Eller, James M Grichnik
Journal: Cancer Research (2015)

Abstract Chromosome instability (CIN) is an important component of multiple malignancies. CIN is linked to drug resistance, tumor grade and aggressiveness. Melanoma is a highly chromosome instable tumor and CIN is a differentiating feature between melanoma and benign nevi. Meiotic proteins are present in melanoma and previous work in our lab suggests a role for these proteins in CIN and that melanoma cell replication has attributes as chromosome pairing and DNA bridging that can be explained by the presence of meiosis proteins. REC8 is a meiotic cohesin which holds sister chromatids together during the first meiotic division, therefore we sought to study the potential role for REC8 in CIN in Melanoma. A model of chromosome instability developed in melanocytic cell lines showed association of REC8 as CIN progressed strengthening the hypothesis that REC8 may be involved in CIN. We overexpressed REC8 in melanoma lines and in E6E7 melanocytes with a TET-inducible system and examined the change in the polyploid population by flow cytometry, cell count and FISH. Results suggest that overexpression of REC8 alone is not sufficient to drive polyploidy in these cell lines. Nevertheless, the association of REC8 with CIN is intriguing and further research in the role of meiosis proteins in melanoma is warranted. Future work will aim at dissecting coexisting meiotic proteins; specially the proteins of the cohesin ring and its regulatory proteins that are also present at high levels in melanoma and could be responsible of chromosome number abnormalities. Citation Format: Julia Escandon, Scott Lindsey, Mark S Eller, James M Grichnik. Meiotic cohesin REC8 associates with chromosome instability in melanoma. [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 3010. doi:10.1158/1538-7445.AM2015-3010
Which AML Subsets Benefit from Leukemic Cell Priming during Chemotherapy? Long-Term Analysis of the ALFA-9802 GM-CSF Study
Authors: Xavier Thomas, Emmanuel Raffoux, Aline Renneville, Cécile Pautas, Stephane de Botton, Thierry de Revel, Oumedaly Reman, Christine Terre, Claude Gardin, Quoc-Hung Le, Nathalie Philippe, Catherine Cordonnier, Jean-Henri Bourhis, Mohamed Elhamri, Sandrine Hayette, Christine Parmentier, Pierre Fenaux, Sylvie Castaigne, Claude Preudhomme, Hervé Dombret
Journal: Blood (2008)
Abstract 2226: PLSCR1- a modifier of TGFβ signaling
Authors: Margaret Klauzinska, Hideaki Karasawa, Maria Cristina Rangel, Nadia Castro, Alyson Baker, Daniel Bertolette, Julie Krask, David Salomon
Journal: Cancer Research (2015)

Abstract The PLSCR family has been proposed to play a role in the redistribution of plasma membrane phospholipids. Recent work on the PLSCRs has revealed their additional functions such as signal transduction and lipid metabolism. The most studied member of this family, PLSCR1, has been shown to partition into lipid rafts implicating it in the regulation and endocytic trafficking of receptor-signaling complexes, e.g. EGFR. Additionally, PLSCR1 has been implicated in tumorigenesis although the exact mechanism of PLSCR1 is still controversial. In a previous study, we identified PLSCRs, as novel Cripto-1 (CR-1) binding proteins that might modulate CR-1-dependent signaling pathways. In this study, we confirmed that PLSCR1 and PLSCR3 bind to Cripto-1 but also that PLSCR1 also inhibits TGFβ signaling via binding to the receptor complexes for the TGFβ superfamily. We also showed that PLSCR1 mediates protein degradation of type I receptors: Alk4 and TGFβRI but not ActRBII, TGFBRII or BMPRb. Additionally, we demonstrated that PLSCR1 is overexpressed in human breast cancer tissue and in human breast cancer cell lines especially in triple-negative MDA-MB-231 and MDA-MB-468. We also showed that knockout of PLSCR1 inhibits migration, invasion and anchorage independent growth of MDA-MB-231, and that TGFβ influences PLSCR1 cellular distribution in those cells. Citation Format: Margaret Klauzinska, Hideaki Karasawa, Maria Cristina Rangel, Nadia Castro, Alyson Baker, Daniel Bertolette, Julie Krask, David Salomon. PLSCR1- a modifier of TGFβ signaling. [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 2226. doi:10.1158/1538-7445.AM2015-2226
Incidence and Prognosis of Psoriasis and Psoriatic Arthritis in Patients Undergoing Bariatric Surgery
Authors: Alexander Egeberg, Jens Ahm Sørensen, Gunnar Hilmar Gislason, Filip Krag Knop, Lone Skov
Journal: JAMA Surgery (2016)

Psoriasis and obesity are strongly linked, and weight loss appears to improve psoriasis symptoms and severity. Bariatric surgery may induce remission of psoriasis, but data are limited to small studies and case series.To examine the incidence and prognosis of psoriasis and psoriatic arthritis in patients undergoing bariatric surgery (gastric bypass and gastric banding).This population-based cohort study used individual-level linkage of administrative and public health registers in Denmark. All Danish citizens who received gastric bypass or gastric banding between January 1, 1997, and December 31, 2012, were included in the study. Data analysis was performed from February 4 to April 14, 2016.The outcomes were incident (new-onset) psoriasis or psoriatic arthritis, or progression to severe psoriasis. Incidence rates per 1000 person-years were calculated, and crude and adjusted hazard ratios (HRs) were estimated by Cox regression models and presented with 95% CIs. The HRs were obtained by comparing the risk in the cohort of patients presurgery and postsurgery, with the presurgery groups serving as the reference groups.We identified 12 364 and 1071 patients receiving gastric bypass and gastric banding, respectively. The gastric bypass subset was composed of 9480 (76.7%) women and 2884 (23.3%) men at the study start; the mean (SD) age of these patients was 27.8 (10.1) years at the study start and 41.0 (10.0) years at the time of surgery. The gastric banding subset was composed of 800 (74.7%) women and 271 (25.3) men; the mean (SD) age of these patients was 32.3 (10.1) years at the study start and 41.7 (10.0) years at the time of surgery. Adjusted HRs of psoriasis were 0.52 (95% CI, 0.33-0.81) and 1.23 (95% CI, 0.40-3.75) for gastric bypass and gastric banding, respectively. Similarly, adjusted HRs of progression to severe psoriasis were 0.44 (95% CI, 0.23-0.86) and 1.18 (95% CI, 0.12-11.49) for gastric bypass and gastric banding, respectively. Adjusted HRs of psoriatic arthritis were 0.29 (95% CI, 0.12-0.71) and 0.53 (95% CI, 0.08-3.56) for gastric bypass and gastric banding, respectively.Gastric bypass was associated with a significantly reduced risk and improved prognosis of psoriasis and psoriatic arthritis, whereas gastric banding was not. This finding may be caused by the postoperative differences in nutrient intake and/or weight loss as well as differences in the secretion of hormones that potentially modulate inflammation.
Thalidomide (T) in Combination with Fludarabine (F) as Initial Therapy for Patients (pts) with Treatment Naïve Chronic Lymphocytic Leukemia (CLL): Results of a Phase I Trial.
Authors: Asher Alban Chanan-Khan, Kena Miller, Alexandra Koryzna, Kenichi Takeshita, Philip McCarthy, Alice Mohr, Kathleen Donohue, Zale P. Bernstein, Arif Alam, Myron S. Czuczman
Journal: Blood (2004)
Extranodal NK/T-Cell Lymphoma, Nasal Type: Experience of Management in a Referral Hospital in a Development Country.
Authors: Humberto Castellanos-Sinco, Silvia Rivas-Vera, Victoria E. Ferrer Argote, Christian Omar Ramos Peñafiel, Ana Carmen Salinas-Torres, Angélica Romo-Jiménez, Merit Hernández-Sánchez, Carlos Martínez-Murillo
Journal: Blood (2009)
Abstract 2097: Grainyhead-like 2 (GRHL2) regulates epithelial plasticity and stemness in oral cancers
Authors: Wei Chen, Shebli Mehrazarin, Ki-Hyuk S Shin, Yi-Ling Lin, Reuben H. Kim, No-Hee Park, Mo K. Kang
Journal: Cancer Research (2015)

Abstract Purpose: Grainyhead-like 2 (GRHL2) is one of the three mammalian homologues of Drosophila Grainyhead involved in epithelial morphogenesis. GRHL2 also controls epithelial cell proliferation and differentiation. Our objective was to evaluate the role of GRHL2 in oral carcinogenesis and the underlying mechanism. Experimental Design: GRHL2 expression was evaluated in multiple oral cancer cell lines and tissues of oral squamous cell carcinomas (OSCCs) by qRT-PCR, western blot assay, immunohistochemistry and laser-captured microdissection assay. The effects of shRNA-mediated GRHL2 knockdown were evaluated by tumor spheroid assay, colony formation assay, gene promoter luciferase assay and immunofluorescent staining and chromatin immunoprecipitation assay. In vivo the effect of GRHL2 loss on cancer cell tumorigenicity was evaluated by tumor xenograft assay. Results: GRHL2 expression was elevated in cells and tissues of oral squamous cell carcinomas (OSCCs) compared with normal counterparts. Knockdown of GRHL2 resulted in the loss of in vivo tumorigenicity, cancer stemness, and epithelial phenotype of oral cancer cells. GRHL2 inhibition decreased oral cancer cell proliferation and colony formation. GRHL2 regulated the expression of miR-200 family and Octamer-binding transcription factor 4 (Oct-4) genes through direct promoter DNA binding. Overexpression of miR-200 genes in the oral cancer cells depleted of GRHL2 partially restored the epithelial phenotype, proliferative rate and cancer stemness. Conclusion: GRHL2 plays pivotal role in the maintenance of the transformed phenotype in OSCCs. Downregulation of GRHL2 leads to the decrease of tumorigenicity, cancer stemness of oral cancer cell, in which miR-200 and Oct-4 genes partially mediate the tumorigenic effects of GRHL2 in OSCC. This study was supported in part by the grants R56DE024593 and Jack Weichman Endowed Fund. Citation Format: Wei Chen, Shebli Mehrazarin, Ki-Hyuk S Shin, Yi-Ling Lin, Reuben H. Kim, No-Hee Park, Mo K. Kang. Grainyhead-like 2 (GRHL2) regulates epithelial plasticity and stemness in oral cancers. [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 2097. doi:10.1158/1538-7445.AM2015-2097
Pharmacogenomics (PGx) Research in the APEX Randomized Multicenter International Phase 3 Trial Comparing Bortezomib and High-Dose Dexamethasone (Dex).
Authors: G. Mulligan, C. Mitsiades, B. Bryant, F. Zhan, W. Cheng, S. Eschrich, B. Burrington, P. Richardson, W. Trepicchio, J. Shaughnessy, L. Bergsagel, A. Damokosh, A. Boral, D. Esseltine, D. Schenkein, K. Anderson
Journal: Blood (2005)
737. RNAi Induced Hepatotoxicity Results from a Functional Depletion of the First Synthesized Isoform of miR-122
Authors: Paul N. Valdmanis, Shuo Gu, Kirk Chu, Lan Jin, Feijie Zhang, Elizabeth M. Munding, Yue Zhang, Yong Huang, Huban Kutay, Kalpana Ghoshal, Leszek Lisowski, Mark A. Kay
Journal: Molecular Therapy (2016)

To ensure success of RNA interference (RNAi) therapeutics, small hairpin RNAs (shRNAs) must co-opt sufficient quantities of the endogenous microRNA machinery to elicit efficient gene knockdown without impeding normal cellular function or causing liver toxicity. Using several recombinant adeno-associated viral (rAAV) vectors expressing shRNAs followed by small RNA sequencing, we determined that hepatic toxicity arises when exogenous shRNA levels exceed 12% of liver microRNAs. High shRNA expression specifically reduced miR-122-5p without affecting any other microRNAs ultimately resulting in functional de-repression of miR-122 target mRNAs. Furthermore, we found that only one isoform of miR-122-5p, 22 nucleotides in length, is displaced in toxic liver samples and that this isoform is the first to be synthesized from miR-122. A causative link between miR-122 reduction and toxicity was established when delivery of an AAV-shRNA expressing miR-122-5p could circumvent toxicity despite reaching 70% of microRNA reads. Consistent with these results, toxicity was not observed in miR-122 knockout mice -which in part adapt to an absence of miR-122 reduction - regardless of the level or sequence of shRNA. Together these results establish the limit to expendable miRNA/RNAi machinery and providing new paradigms for the role of miR-122 in liver homeostasis.
P08.41 Development of a novel TERT-targeting therapy for glioblastomas
Authors: K. Ichimura, M. Takahashi, Y. Matsushita, Y. Maida, M. Yasukawa, M. Hayashi, A. Hamada, R. Nishikawa, Y. Narita, K. Masutomi
Journal: Neuro-Oncology (2016)

Introduction:
Approximately 60–80% of GBM harbour mutations in the promoter region of TERT that leads to its upregulation, making it the most common single genetic abnormalities in GBM. TERT, a reverse-transcriptase subunit of telomerase, has been an attractive candidate for therapy target because of their observed upregulation in a wide variety of cancers, including GBMs, a phenomenon that presumably helps maintain telomeres for their indefinite proliferation. However, no targeted therapy against telomerase has been successful so far, possibly because telomerase inhibition may not be necessarily expected to immediately suppress proliferation when telomere has already been elongated. It has been reported recently that TERT has an RNA-dependent RNA polymerase (RdRP) activity independent of its function at telomeres. The TERT-RdRP activity appears to be involved in controlling cell cycle and maintenance of stem cell phenotype, suggesting that TERT may be directly targeted to suppress tumour cell proliferation. Through drug screening, we have previously identified eribulin as a specific inhibitor for RdRP activity of TERT. Eribulin does not affect the telomerase activity at the concentration to inhibit the RdRP activity. In order to develop a novel TERT-targeted therapy against GBM, we investigated the anti-tumour efficacy of eribulin in cultured and xenografted GBM cells.
Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines
Authors: Zahid Padamsey, Lindsay McGuinness, Scott J. Bardo, Marcia Reinhart, Rudi Tong, Anne Hedegaard, Michael L. Hart, Nigel J. Emptage
Journal: Neuron (2016)

Lysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca2+ stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+ release from lysosomes in the dendrites. This Ca2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+ signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling.
FOLFIRINOX for locally advanced and metastatic pancreatic ductal adenocarcinoma
Authors: Hiroyuki Hisai, Sakurai Tamaki, Ikeda Yuuki, Koshiba Yutaka, Sato Masafumi, Kawasaki Ryosuke, Gyobu Hiroshi, Miyazaki Etsu, Hirako Tasuku, Miura Shogo
Journal: Annals of Oncology (2015)
Commentary on “Epithelial–to–Mesenchymal Transition Contributes to Drug Resistance in Pancreatic Cancer”
Authors: Jessica A. Beach, David D.L. Bowtell
Journal: Cancer Research (2016)

See related article by Arumugam et al., [Cancer Res 2009;69:5820–8][1] .

Visit the Cancer Research 75th Anniversary [timeline][2].

First described in the early 1980s, epithelial-to-mesenchymal transition (EMT) is a process wherein epithelial cells lose their differentiated characteristics, such