tbuckley/cabot-search huggingface dataset:
NIMG-12GENE SIGNATURES ASSCOCIATED WITH DIFFUSION MRI ADC MAPPING OF GLIOBLASTOMA EDEMA/TUMOR INVASION
Authors: Masumeh Hatami, Pascal O. Zinn, Rivka R. Colen
Journal: Neuro-Oncology (2015)

BACKGROUND: Diffusion MR imaging (dMR) is widely used in clinical practice and captures a distinct molecular/cellular features of tumor tissue. The aim of this study is to correlate pretreatment tumor Apparent Diffusion Coefficient (ADC), measured by diffusion magnetic resonance (dMR) imaging with overall survival in patients with glioblastoma and determine its association with gene signatures. METHODS: We retrospectively identified 37 treatment-naive glioblastoma patients from The Cancer Genome Atlas (TCGA) whom had gene expression profiles and corresponding dMR imaging available in The Cancer Imaging Archive (TCIA). ADC mean were measured in edema/tumor invasion of GBM lesions and contralateral normal brain tissue. To normalize ADC values, ADC mean of edema/tumor invasion regions were divided by the contralateral ADC means. Using decision tree clustering method, patients categorized based on normalized ADC mean into high vs low groups. Kaplan-Meyer survival analysis was used to determine the difference of overall survival between the two groups of patients. Imaging genomic analysis was subsequently performed using GenePattern Comparative Marker Selection module (Broad Institute). To identify the associated gene network, the top 100 most positively and the top 100 most negatively correlated genes in the high group versus the low group were then analyzed with Ingenuity Pathway Analysis. RESULTS: Based on decision tree analysis, normalized ADC mean cutoff of 19.48 was used to categorize patients to high (n = 6) versus low (n = 31) groups. Kaplan-Meier analysis showed the patients with high normalized ADC mean had significantly (p = 0.02) better overall survival than the patients with low normalized ADC mean. Median survival in high and low group was 747 and 394 days, respectively. There was a significant genomic signature, associated with high vs low groups. The validation of these analyses was done in a separate group of glioblastoma patients. CONCLUSIONS: dMR characteristics can identify highly significant survival differences and specific genomic signature.
Treatment of severe atopic dermatitis with ustekinumab: a case series of 10 patients
Authors: E. Nic Dhonncha, J. Clowry, M. Dunphy, C. Buckley, S. Field, L. Paul
Journal: British Journal of Dermatology (2016)

Atopic dermatitis (AD) is a common, chronic pruritic inflammatory condition, with an estimated prevalence of 15-30% in children, and 2-10% in adults.1 Pathogenesis of AD is complex, and remains incompletely understood. Th1, Th2 and Th17 have been reported to play a role.2 Treatment of severe AD is challenging, with currently licensed systemic agents being limited by adverse effects and suboptimal therapeutic responses.

This article is protected by copyright. All rights reserved.
Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration
Authors: Debbie L.C. van den Berg, Roberta Azzarelli, Koji Oishi, Ben Martynoga, Noelia Urbán, Dick H.W. Dekkers, Jeroen A. Demmers, François Guillemot
Journal: Neuron (2016)

Mutations in NIPBL are the most frequent cause of Cornelia de Lange syndrome (CdLS), a developmental disorder encompassing several neurological defects, including intellectual disability and seizures. How NIPBL mutations affect brain development is not understood. Here we identify Nipbl as a functional interaction partner of the neural transcription factor Zfp609 in brain development. Depletion of Zfp609 or Nipbl from cortical neural progenitors in vivo is detrimental to neuronal migration. Zfp609 and Nipbl overlap at genomic binding sites independently of cohesin and regulate genes that control cortical neuron migration. We find that Zfp609 and Nipbl interact with the Integrator complex, which functions in RNA polymerase 2 pause release. Indeed, Zfp609 and Nipbl co-localize at gene promoters containing paused RNA polymerase 2, and Integrator similarly regulates neuronal migration. Our data provide a rationale and mechanistic insights for the role of Nipbl in the neurological defects associated with CdLS.
Effect of metformin alone and in combination with 5-fluorouracil (5FU), oxaliplatin (O) and irinotecan (I) on human colon cancer cell lines.
Authors: A. Kunthur, A. Aldwairi, F. Simmen, R. Govindarajan
Journal: Journal of Clinical Oncology (2011)

e13041 Background: Metformin, an oral hypoglycemic agent used in the treatment of type II diabetes mellitus has been shown to decrease the incidence of colorectal cancer and may prolong survival in diabetic patients with colon cancer. Efficacy of metformin, in combination with chemotherapeutic agents, for colorectal cancer has not been previously examined. This study was conducted to compare growth inhibitory effects of metformin alone, in combination with chemotherapeutic agents on colon cancer cell lines. Methods: HT 29 and HCT 116 human colon cancer cell lines were treated with metformin alone at 1 mM concentration, in combination with single agents 5 FU (20 µM), I (5 µM), O (5 µM), and in combination with pairs of drugs. Growth inhibition was monitored using MTT assay. The experiment was performed in sequential design; the cells were first pretreated with metformin and then treated with chemotherapeutic agents and in a concurrent design, the cells simultaneously exposed to metformin and chemotherapeutic agents. Results: Metformin significantly decreased cell viability as a single agent and had an additive effect when combined with single agent and combination chemotherapeutic agents in the sequential experiment. On concurrent exposure, metformin showed an additive effect when combined with single agents but did not confer any extra benefit when added to the combination of 5 FU+I or 5 FU+ O. Conclusions: Metformin has antineoplastic activity as a single agent and enhanced the activity of single agent and combination chemotherapy when cells were pretreated with metformin. Percent viable cells: Concurrent exposure Percent viable cells: Sequential exposure Drug H29 P HCT116 P H29 p HCT116 P Control 100% 100% 100% 100% M 55 <0.001 58 <0.001 29 <0.001 64 0.001 5FU 49 <0.001 43 <0.001 86 0.103 89 0.094 M +5FU 42 <0.001 39 <0.001 24 <0.001 45 <0.001 O 96 0.375 71 0.001 80 0.055 89 0.389 O+M 58 <0.001 49 <0.001 23 <0.001 57 <0.001 I 75 0.296 79 0.055 79 0.028 85 0.037 I+ M 62 <0.001 45 0.008 42 0.022 45 <0.001 5FU+I 46 <0.001 47 <0.001 37 <0.001 69 0.004 5FU+I+M 47 0.002 37 <0.001 14 <0.001 41 <0.001 5FU+O 23 <0.001 25 <0.001 55 0.003 75 0.009 5FU+O+M 32 <0.001 33 <0.001 14 <0.001 43 <0.001
The Aurora Kinase Inhibitor MLN8237 Has Potent Anticancer Activity in CML and Ph+ ALL Models and Significantly Increases the Efficacy of Nilotinib
Authors: Steffan T. Nawrocki, Ernest Medina, Sabrina Smith, Ronan Swords, Kevin Kelly, Swaminathan Padmanabhan, Jeffrey Ecsedy, Francis J Giles, Jennifer Carew
Journal: Blood (2008)
Abstract 4887: TCR profiling of T lymphocytes in ovarian tumors and malignant ascites using next-generation sequencing
Authors: Miran Jang, Poh-Yin Yew, Kosei Hasegawa, Yuji Ikeda, Keiichi Fujiwara, Gini F. Fleming, Yusuke Nakamura, Jae-Hyun Park
Journal: Cancer Research (2015)

Abstract Tumor-infiltrating lymphocytes (TILs) are often observed in many types of solid tumors and considered to reflect the host immune system that eliminates or protects tumor cells. Many studies indicated that higher TIL infiltration is correlated with better prognosis of patients. In addition, some studies suggested that T cells in malignant ascites are associated with clinical outcome. Thus, it is important to define the immune microenvironment in malignant effusions through characterization of T cell repertoire. We here applied a high-throughput next generation sequencing method to characterize T cell receptor (TCR) sequences of a set of primary cancer, ascites, and blood from 12 ovarian cancer patients. We also analyzed the TCR cDNAs of the T cell subtype populations in malignant fluids from 3 ovarian cancer patients. We observed the clonal expansion of certain T cells in tumor and ascites, and found the enriched TCR sequences representing the distinct profiles. Moreover, we investigated TCR sequence signature of CD4+, CD8+, and CD4+CD25+ regulatory T cells in malignant effusion and identified clonally expanded T cell populations. Interestingly TCR sequences among three T cell subsets were almost mutually exclusive. Although the functional studies of clonally expanded T cell populations are definitely required, our approach offers the detailed characterization of T cell immune microenvironment for investigating a beneficial immune response in the host immune system and further contributes to the improvement of cancer immunotherapy. Citation Format: Miran Jang, Poh-Yin Yew, Kosei Hasegawa, Yuji Ikeda, Keiichi Fujiwara, Gini F. Fleming, Yusuke Nakamura, Jae-Hyun Park. TCR profiling of T lymphocytes in ovarian tumors and malignant ascites using next-generation sequencing. [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 4887. doi:10.1158/1538-7445.AM2015-4887
A Phase I Study of the Histone Deacetylase Inhibitor MGCD0103 (MG-0103) Given as a Three-Times Weekly Oral Dose in Patients with Leukemia or Myelodysplastic Syndromes (MDS).
Authors: Guillermo Garcia-Manero, Mark Minden, Zeev Estrov, Srdan Verstovsek, Jackie Fiorentino, Hagop Kantarjian, Gregory Reid, Robert E. Martell
Journal: Blood (2005)
Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study
Authors: G.A. McArthur, M. Maio, A. Arance, P. Nathan, C. Blank, M.-F. Avril, C. Garbe, A. Hauschild, D. Schadendorf, O. Hamid, M. Fluck, M. Thebeau, J. Schachter, R. Kefford, M. Chamberlain, M. Makrutzki, S. Robson, R. Gonzalez, K. Margolin
Journal: Annals of Oncology (2016)
Identification of Phosphatidylinositol 4-Kinase Type II β as the First HLA Class II Associated Minor Histocompatibility Antigen Involved in Graft Versus Leukemia Reactivity.
Authors: Marieke Griffioen, Edith D. van der Meijden, M. Willy Honders, Caroline Rutten, Simone A.P. van Luxemburg-Heijs, Peter A. von dem Borne, Roelof Willemze, J.H. Frederik Falkenburg
Journal: Blood (2007)
Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Japanese subgroup analysis of the phase III REACH trial
Authors: Shinichi Ohkawa, Takuji Okusaka, Masatoshi Kudo, Etsuro Hatano, Hirofumi Fujii, Akihide Masumoto, Junji Furuse, Yoshiyuki Wada, Hiroshi Ishii, Shuntaro Obi, Kuniaki Arai, Seiji Kawazoe, Osamu Yokosuka, Masafumi Ikeda, Katsuaki Ukai, Sojiro Morita, Hiroya Asou, Paolo B. Abada, Ling Yang, Andrew X. Zhu
Journal: Annals of Oncology (2015)
731. High-Fidelity CRISPR-Cas9 Nucleases with No Detectable Genome-Wide Off-Target Effects
Authors: Benjamin P. Kleinstiver, Vikram Pattanayak, Michelle S. Prew, Shengdar Q. Tsai, Nhu T. Nguyen, J. Keith Joung
Journal: Molecular Therapy (2016)

CRISPR-Cas9 nucleases are widely used for genome editing but can induce unwanted off-target mutations at genomic locations that resemble the intended target. These so-called off-target effects can confound research applications and are important considerations for potential therapeutic use. Existing strategies for reducing genome-wide off-targets of the broadly used Streptococcus pyogenes Cas9 (SpCas9) have thus far proven to be imperfect by possessing only partial efficacy and/or other limitations that constrain their use. Here we describe a high-fidelity variant of SpCas9, called SpCas9-HF1, that contains alterations in the amino acid sequence designed to reduce non-specific contacts to the target strand DNA. SpCas9-HF1 retains on-target activities comparable to wild-type SpCas9 with >85% of the 37 single-guide RNAs (sgRNAs) tested in human cells. Strikingly, with eight different sgRNAs targeted to standard non-repetitive sequences in human cells, SpCas9-HF1 rendered all or nearly all off-target events imperceptible by genome-wide break capture and targeted sequencing methods. Even for atypical, repetitive target sites, the vast majority of off-targets induced by SpCas9-HF1 were not detected. With its exceptional precision, SpCas9-HF1 provides an important and easily employed alternative to wild-type SpCas9 that can eliminate off-target effects when using CRISPR-Cas9 for research and therapeutic applications. Our findings also suggest a general strategy for improving or optimizing the genome-wide specificities of other Cas9 orthologues and engineered variants.
Breaking Immune Tolerance to Granule Proteases with Full-Length Antigen Vaccine in Humanized Transgenic Mice Reveals Alternative Antigen Processing and Immunodominance Heirarchy Applicable to Clinical Immunotherapy.
Authors: J. Diamond Don, Wendi Zhou, Tumul Srivastava, Ravindra Rawal, Katharine Hagan, Helen A Andersson, J. N. Cooper Laurence, Jeffrey J. Molldrem, Simon F. Lacey
Journal: Blood (2009)
Quantitative gene expression in primary and highest Gleason pattern cancer specimens identifies genes associated with clinical recurrence and prostate cancer–specific survival after radical prostatectomy.
Authors: E. A. Klein, S. M. Falzarano, T. Maddala, M. Lee, R. J. Pelham, W. F. Novotny, S. Shak, C. Magi-Galluzzi
Journal: Journal of Clinical Oncology (2011)

4663 Background: Prostate biopsy may not adequately sample small, secondary or tertiary Gleason pattern tumors which can drive clinical outcome. We conducted a study to determine whether tumor-derived gene expression profiling could identify a distinct underlying biology associated with clinical recurrence (cR) after radical prostatectomy (RP) across both the primary and highest Gleason pattern (GP) samples. Methods: All patients (pts) with clinical stage T1/T2 prostate cancer treated with RP at Cleveland Clinic from 1987 to 2004 were identified (n~2,600). A cohort sampling design was used to select 127 patients with cR and 374 patients without cR after RP. Each patient had two spatially distinct tumor specimens sampled that included the primary GP (PGP) and the highest GP (HGP). Surgical GS and clinical data were centrally reviewed. RNA was extracted from 6 manually dissected 10 μm fixed paraffin embedded tissue sections obtained from the RP tumor specimens and expression of 732 cancer-related and reference genes was quantified using RT-PCR. Clinical recurrence−free interval (cRFI) and prostate cancer-specific survival (PCSS) were analyzed using Cox PH regression. Results: Blocks from 441 patients were evaluable. Median F/U was 5.8 years. Pts were mostly Caucasian (83%), clinical stage T1 (66%), had baseline PSA <10 ng/mL (82%), and surgical GS ≤7 (87%). We identified 235 genes associated with cRFI in both the PGP and HGP samples, well in excess of the number expected by chance. 75% of these genes were also associated with PCSS. Many genes remained significantly associated with cRFI in multivariate analyses adjusted for pathologic T-stage, GS, AUA risk group and CAPRA score (221, 99, 244, and 271 genes respectively). Conclusions: Gene expression analysis using quantitative RT-PCR identified a large number of genes, and underlying biology, that are strongly associated with clinical recurrence in both the primary and the highest Gleason pattern that adds prognostic value beyond clinical and pathology covariates.
Detailed Long-Term Follow up of Treatment-Naive Chronic Lymphocytic Leukemia (CLL) Patients in the Australasian Leukemia and Lymphoma Group (ALLG) CLL5 Trial; Data on 17 (15% of Total Cohort) Patients from a Single-Institution
Authors: Suneet Sandhu, Naomi Mackinlay, Luke Coyle, Giles Best, Stephen Mulligan
Journal: Blood (2015)
Abstract 2937: MEK/ERK inhibitor GDC-0623 dephosphorylates and accumulates BIM that enables a synergistic apoptosis with the Bcl-xL antagonist, ABT-263, in mutant <i>KRAS</i> colorectal cancer cells
Authors: Aziz Zaanan, Koichi Okamoto, Hisato Kawakami, Shengbing Huang, Frank Sinicrope
Journal: Cancer Research (2015)

Abstract Background. Oncogenic KRAS mutations occur in nearly one-half of colorectal cancers (CRC) where they contribute to de novo apoptosis resistance and treatment failure. Inhibition of MEK/ERK is a promising strategy to sensitize KRAS mutant tumors to apoptosis that may involve upregulation of pro-apoptotic BH3-only proteins, including BIM. However, BH3-only proteins can be neutralized by anti-apoptotic Bcl-xL that we found was upregulated in isogenic KRAS mutant compared to wild-type HCT116 and DLD1 CRC cells. Aims. We determined the ability and mechanism by which a novel MEK/ERK inhibitor, GDC-0623, can induce BIM to promote apoptotic signaling. A strategy of concurrent induction of BH3-only proteins and antagonism of Bcl-xL was studied to overcome mutant KRAS-mediated apoptosis resistance. Results. Using isogenic KRAS HCT116 cells and KRAS mutant SW620 cells, we found that GDC-0623 can potently induce the BH3-only protein BIM, and to a lesser extent BIK, in both KRAS wild-type and mutant cells. Only KRAS mutant cells remained resistant to GDC-0623-induced apoptosis. Knockdown of Bcl-xL or use of a BH3 mimetic drug, ABT-263, sensitized KRAS mutant cells to GDC-0623-mediated apoptosis. GDC-0623 and ABT-263 were shown to interact synergistically to promote apoptosis in KRAS mutant cells. Dependence on BIM or BIK for synergy between GDC-0623 and ABT-263 was shown by shRNA knockdown that each attenuated drug-induced apoptosis. Mechanistically, ABT-263 treatment was shown to release BIM from its binding to Bcl-xL using immunoprecipitation. The ability of GDC-0623 to induce apoptosis occurred via BIM that was phosphorylated by MEK/ERK activation leading to BIM degradation. GDC-0623 was shown to dephosphorylate BIM at serine 69 in cells with wild-type BIM or a phospho-mimic mutation (S69E). However, GDC-0623's ability to dephosphorylate BIM was lost in cells containing a phosphorylation-defective BIM mutation (S69G) that showed delayed BIM degradation. Conclusion. GDC-0623 was shown to dephosphorylate BIM to enhance its accumulation and to promote apoptosis. Concurrent induction of BIM/BIK and antagonism of Bcl-xL can overcome mutant KRAS-mediated apoptosis resistance, suggesting a promising therapeutic strategy against KRAS mutant CRCs. Note: This abstract was not presented at the meeting. Citation Format: Aziz Zaanan, Koichi Okamoto, Hisato Kawakami, Shengbing Huang, Frank Sinicrope. MEK/ERK inhibitor GDC-0623 dephosphorylates and accumulates BIM that enables a synergistic apoptosis with the Bcl-xL antagonist, ABT-263, in mutant KRAS colorectal 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 2937. doi:10.1158/1538-7445.AM2015-2937
96. Genomic Integration Profile of AAVHSC Vectors in Human CD34+ Long-Term Engrafted Hematopoietic Stem Cell Xenografts in Immune-Deficient Mice
Authors: Manasa Chandra, Tahira Ul-Hasan, Laura J. Smith, K.K. Wong, Saswati Chatterjee
Journal: Molecular Therapy (2015)

Adeno-associated virus vectors (AAV) are proving to be promising and powerful for gene delivery due to their ability to safely transduce both non-dividing and dividing cells. While AAV mainly persists in episomal copies in non-dividing cells, genomic integration has been reported including in CD34+ hematopoietic stem cells (HSCs). Characterizing the vector integration profile is important to ensure safety since genomic integration has the potential for inducing insertional mutagenesis and genotoxicity. The absence of genotoxicity of AAV has been documented in multiple studies. Our lab has recently described the isolation and gene transfer properties of human HSC derived AAVs (AAVHSCs) (Smith LJ, et al. Mol Therapy 2014). To test the ability of the AAVHSCs to transduce long-term engrafted HSCs, we transduced human CD34+ cells with AAV vectors encoding a luciferase transgene prior to transplantation into irradiated immunodeficient NOD/SCID mice. Through serial bioluminescent imaging, we found that the AAVHSCs supported higher levels of expression than AAV2, 7 and 8. Of the AAVHSC serotypes tested, AAVHSC17 was found to support the highest level of transgene expression in vivo, for at least six months post-transplantation. Since vector genomes were found to persist in both long-term engrafted CD34+ cells as well as their differentiated hematopoietic progeny, we hypothesized that the vector genomes likely persisted as chromosomal integrants since episomal copies would have been lost during mitosis. Here, we evaluated the vector genome integration profile in the long-term engrafted CD34+ HSCs transduced with AAVHSC17. High molecular weight DNA was extracted from flow sorted human CD34+ cells isolated from engrafted mouse marrow and sonicated to fragment the DNA before ligation of double stranded DNA adaptors. Using LM-PCR we amplified AAV-chromosomal sequences using AAV-specific and adaptor-specific primers, and further enriched vector-chromosome junctions with nested PCR. The PCR generated library was then used for paired-end Illumina sequencing. The sequence reads were paired using CLC Genomics Workbench. High-throughput analysis resources including PLAN, BLAST (NCBI), and ENSEMBL were used to determine the locations of the AAV-chromosomal junctions. AAV integration was found to occur randomly throughout the genome, including the X and Y chromosomes. Similar to previous studies, AAV integration junctions were largely found in non-coding and intronic regions. Integration was also found to occur within microsatellite repeat regions and GC rich regions. Thus far, no integration events have been found in coding regions or near oncogenes. Due to the lack of detectable genotoxicity resulting from AAV integration in CD34+ HSCs and the ability to support long term in vivo transgene expression, we conclude that these vectors are well-suited for stem cell gene delivery.
C/EBPβ Isoforms Distinctively and Collaboratively Regulate the Behavior of Hematopoietic Stem and Progenitor Cells in Regenerative Conditions
Authors: Atsushi Sato, Hideyo Hirai, Asumi Yokota, Akihiro Tamura, Tsukimi Shoji, Takahiro Kashiwagi, Masaki Iwasa, Aya Fujishiro, Yasuo Miura, Taira Maekawa
Journal: Blood (2015)
Peptidylarginine deiminase 4 promotes age-related organ fibrosis
Authors: Kimberly Martinod, Thilo Witsch, Luise Erpenbeck, Alexander Savchenko, Hideki Hayashi, Deya Cherpokova, Maureen Gallant, Maximilian Mauler, Stephen M. Cifuni, Denisa D. Wagner
Journal: The Journal of Experimental Medicine (2016)

Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4-/- mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4-/- mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4-/- myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.