tbuckley/cabot-search huggingface dataset:
OC-039 Altered gene expression levels of MAD2, BUB1, aurora kinase A and B in early gastric cancers
Authors: A Somasekar, A Chatterjee, L Williams, P Griffiths, J Williams, G Jenkins
Journal: Gut (2010)

<h3>Introduction</h3> Losses and/or gains of whole chromosomes (aneuploidy) are extremely common in most cancers. Indeed aneuploidy is thought to occur early in carcinogenesis and the genetic instability induced is thought to provide a pool of selectable clones for tumour evolution. We have been interested in aneuploidy as a biomarker for GI tract cancer for some time. It is believed that alterations in the expression of key components of the mitotic checkpoint drive aneuploidy, by impairing the ability of this checkpoint to prevent chromosome mis-segregation. Here we aimed to correlate gene expression levels of the mitotic checkpoints MAD2, Bub1, aurora kinase A and B with aneuploidy levels and histology in premalignant gastric tissues. <h3>Methods</h3> We collected over 50 cytology brush samples of gastric mucosa during routine endoscopic examination. We examined aneuploidy levels in these exfoliated cells using fluorescent in situ hybridisation, specifically looking at copy numbers of chromosome 1. Concurrently, during endoscopy, biopsy samples were obtained from the same gastric epithelium for histological assessment and for CLO testing and further biopsies were obtained and used to extract RNA to determine mitotic checkpoint gene expression levels using the real-time PCR. Specifically the expression levels Mad2, Bub1, aurora kinase A and B were assessed. <h3>Results</h3> Aneuploidy levels mirrored histological progression in the stomach as previously described (from an average of 2.6% in normal gastric epithelium to over 6% in intestinal metaplasia/atrophic gastritis). RNA was extracted from 46 samples for mitotic checkpoint gene expression analysis. Mad2 and Bub1 expression levels were found to be decreased significantly in the small number of samples with intestinal metaplasia. We also demonstrated that the levels of Mad2 and Bub1 were also diminished in the 28 patients with gastritis. Conversely, Aurora kinase A and B were upregulated in the H pylori infected tissues in particular, compared to histologically normal tissue. Comprehensive data analysis is now underway comparing mitotic checkpoint expression to histology, aneuploidy level and to key clinical parameters. <h3>Conclusion</h3> Mitotic checkpoint dysregulation occurs in pre-malignant gastric tissue concurrently with rising levels of aneuploidy. These mitotic checkpoint abnormalities may underlie the induction of aneuploidy and may represent the mechanism by which chromosomal instability is induced in early neoplasia.
Monitoring Trough Concentration of Voriconazole Is Important to Ensure Successful Antifungal Therapy and to Avoid Hepatic Damage in Patients with Hematological Disorders.
Authors: Yasuhito Nannya, Koki Ueda, Keiki Kumano, Akira Hangaishi, Tsuyoshi Takahashi, Yoichi Imai, Mineo Kurokawa
Journal: Blood (2009)
Abstract 4564: TCF4 is a molecular target of resveratrol-induced apoptosis in colon cancer
Authors: Jin Boo Jeong, Kui-Jin Kim, Seong-Ho Lee
Journal: Cancer Research (2015)

Abstract TCF-4 (T cell factor-4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors. Although dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer, the role of TCF4 in transcriptional regulation of their target gene remained poorly understood. The current study was performed to see if TCF4 could be molecular target for anti-cancer compounds. Several phytochemicals including resveratrol repressed expression of TCF4 in human colorectal cancer cells. Resveratrol decreases accumulation of ectopically expressed TCF4 protein without changes of TCF4 transcription. Pre-treatment of MG-132 and lactacystin ameliorates resveratrol-stimulated downregulation of TCF4. Resveratrol-treated cells showed longer half-life of TCF4. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK and p38-dependent pathways. Knockdown of TCF4 decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides new mechanistic link between TCF4 downregulation and significant benefits of phytochemicals. Citation Format: Jin Boo Jeong, Kui-Jin Kim, Seong-Ho Lee. TCF4 is a molecular target of resveratrol-induced apoptosis in 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 4564. doi:10.1158/1538-7445.AM2015-4564
The Tyrosine Kinase Src Regulates Adhesion and Survival in Waldenström Macroglobulinemia
Authors: Hai T. Ngo, Mena Farag, Xiaoying Jia, Nicolas Burwick, Molly R. Melhem, Xavier Leleu, Judith Runnels, Abdel Kareem Azab, Aldo M. Roccaro, Feda Azab, Antonio Sacco, Phong Quang, Yu-Tzu Tai, Kenneth C. Anderson, Irene M. Ghobrial
Journal: Blood (2008)
Lenalidomide and Dexamethasone Promote Erythropoiesis in Both Normal and RPS14 and RPS19 shRNA Infected Human CD34+ Cells: Implications for Therapy of Myelodysplastic Syndrome and Diamond-Blackfan Anemia.
Authors: Anupama Narla, Shilpee Dutt, J. Randall McAuley, Benjamin L. Ebert
Journal: Blood (2009)
Clinical Significance of Cardiac Co-Morbidities and Risk Factors for Patients Treated with Imatinib.
Authors: Asifa Malik, Jorge E. Cortes, Hagop Kantarjian, Gloria Mattiuzzi, Gloria Iliescu, Alessandra Ferrajoli, Gautam Borthakur, Tapan Kadia, Susan O'Brien
Journal: Blood (2010)
79. Vector Dose Delineates Between Chronic, Non-Functional CD8+ T Cell Response and Tolerance to the Transgene Product Upon Liver Gene Transfer
Authors: Sandeep Kumar, Brad E. Hoffman, Roland W. Herzog
Journal: Molecular Therapy (2016)

The liver is characterized by a microenvironment that promotes immune tolerance, which can be exploited by gene therapy. In the case of hepatitis viral infections such as HBV or HCV however, ineffective or non-functional responses can result in chronic disease. To understand the parameters and mechanisms that govern the CD8+ T cell response to a virally encoded antigen expressed in the liver, we administered an adeno-associated virus expressing ovalbumin (AAV8-EF1α-ovalbumin) to immune competent C57BL/6J mice at various doses (low: 1×108 vg, medium: 1×109 vg, and high: 1×1010 vg). Interestingly, all doses resulted in sustained vector-dose dependent systemic ova expression, albeit with distinct immune profiles. At the low dose and the high doses, no response to ova was observed. At the medium dose, circulating ova-specific CD8+ T cells were detected in 40-50% of mice at high frequency (5-35%) by tetramer stain. These emerged within 1 month and, while declining in frequency over time, can persist for up to one year. Despite their inefficiency in eliminating vector-derived ova expression, functional assays demonstrated that induced CD8+ T cells retained cytolytic activity to SIINFEKL (the dominant ovalbumin MHC class I epitope in C57BL/6J mice) peptide-loaded target cells in vivo or in vitro, and that they produced Th1 type cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in response to ex vivo stimulation with SIINFEKL epitope. Further phenotypic characterization revealed that most of these cells expressed PD-1 and 2B4. Other markers of exhaustion such as CD160, LAG3 and TIM3 were expressed to a lesser extent. Cells acquired memory phenotype over time as judged by CD44, CD62L, and CCR7 markers. Since higher vector doses failed to induce the CD8+ T cell response entirely, a potent antigen-dependent "off switch" has to exist in the liver. Previously, we and others identified FoxP3+ Treg, activation induced apoptotic cell death, and expression of the immune suppressive cytokine IL-10 as contributors to immune tolerance induction by hepatic gene transfer. Therefore, we used Foxp3-DTR mice (for transient depletion of Treg), FasL−/−, and IL-10−/− mice to determine if these pathways were required in preventing ova-specific CD8+ T cell activation in the high-dose group. Transient depletion of Foxp3+ Treg in Foxp3-DTR mice led to a low but detectable CD8+ T cell response in all animals. In contrast, only 1/5 (20%) of FasL−/− or IL-10−/− mice developed a response. Therefore, it is likely that multiple (and perhaps redundant) mechanisms work in concert to achieve high-dose tolerance to proteins expressed in the liver. These results have implications for viral infections of the liver and for gene and cell therapies, illustrating the potential for chronic albeit only partially functional T cell responses at low doses, which can be entirely prevented at sufficient antigen doses.
Potential New Treatment Option for Iron Deficiency Anemia Patients with a History of Unsatisfactory Oral Iron Therapy- Results of a Phase III, Randomized, Open-Label, Active-Controlled Trial of Ferumoxytol.
Authors: David Hetzel, Audrone Urboniene, Kristine Bernard, William Strauss, Michael Cressman, Zhu Li, Lee F. Allen
Journal: Blood (2012)
In Vitro Effects of PI3Kδ Inhibitor GS-1101 (Cal-101) in Acute Lymphoblastic Leukemia (ALL)
Authors: Nathalie Y Rosin, Stefan Koehrer, Ekaterina Kim, Susan O'Brien, William G. Wierda, Deborah A. Thomas, Zeev Estrov, Hagop M. Kantarjian, Brian J. Lannutti, Jan A. Burger
Journal: Blood (2012)
<i>TRPM8</i>polymorphisms associated with increased risk of IBS-C and IBS-M
Authors: Maria Henström, Fatemeh Hadizadeh, Arthur Beyder, Ferdinando Bonfiglio, Tenghao Zheng, Ghazaleh Assadi, Joseph Rafter, Luis Bujanda, Lars Agreus, Anna Andreasson, Aldona Dlugosz, Greger Lindberg, Peter T Schmidt, Pontus Karling, Bodil Ohlsson, Nicholas J Talley, Magnus Simren, Susanna Walter, Mira Wouters, Gianrico Farrugia, Mauro D'Amato
Journal: Gut (2016)

Recently in Gut , genetic variation affecting ion channels activity has been highlighted in relation to bowel function and the biology of stool frequency.1 It is also known that 2% of patients with IBS carry functional missense mutations in the voltage-gated channel NaV1.5 ( SCN5A gene).2 Hence, channelopathies represent potential abnormalities underlying GI dysfunction and IBS. We inspected data from our previous genome-wide association study (GWAS) of IBS,3 in relation to 27 genes whose ion channel products contribute to GI sensorimotor development and function, visceral sensation and GI motility (see online supplementary table S1). Significant (uncorrected) results were detected for four genes (calcium voltage-gated channels CACNA1A and CACNA1E , and transient receptor potential channels TRPV3 and TRPM8 ; see online supplementary figure S1), which were selected for replication analyses in an independent set of IBS cases (N=386) and controls (N=357) (see online supplementary material methods). A sex-adjusted logistic regression analysis of genotype data from this cohort (see online supplementary material methods) detected significant associations for …
Abstract 716: Targeting Mek-Erk pathway abrogates hypoxia-mediated lapatinib resistance in ErbB2-positive breast cancer cells
Authors: Sergey Karakashev, Mauricio Reginato
Journal: Cancer Research (2015)

Abstract Overexpression/amplification of the tyrosine kinase ErbB2 is often observed in breast cancers. ErbB2 expression activates EGFR signaling pathway promoting tumorigenesis. Breast cancer ErbB2-positive patients are treated with lapatinib, a dual EGFR/ERBB2 inhibitor. Despite lapatinib clinical efficacy, acquired resistance has been reported and its mechanism is poorly understood. Another factor that is associated with mammary tumors is hypoxia. Hypoxia stabilizes hypoxia inducible factor 1 (HIF-1), a transcription factor that regulates cell growth, proliferation and survival. As a result, hypoxic tumors are often chemoresistant. Here, we show that hypoxia decreases lapatinib-mediated growth inhibition and apoptosis in three-dimensional cultures. In agreement with this data, hypoxia also promotes activation of signaling pathways downstream from ErbB2/EGFR including AKT and ERK in the presence of lapatinib. This protective effect depends on HIF-1 and can be abrogated by HIF-1 RNAi. Moreover stable overexpression HIF-1 in ErbB2-expressing cells under normoxic conditions is sufficient to rescue cell proliferation and survival and maintain ERK and AKT signaling in the presence of lapatinib. We also show that activation of ERK signaling is required for hypoxia-mediated lapatinib resistance and inhibition of MEK (a kinase upstream of Erk) reverses hypoxia protective effect on ErbB2-expressing cells. One potential mechanism of how hypoxia/HIF-1 may lead to activation of ERK pathway is via regulation of dual-specificity phosphatase 2 (DUSP2). DUSP2 is a negative regulator of ERK pathway. Here we demonstrate that cells exposed to hypoxia have decreased levels of DUSP2 and it correlate with increased activation of Erk signaling. Moreover, reducing DUSP2 expression alone in ErbB2-positive breast cancer cells is sufficient to reduce lapatinib-mediated effects. And DUSP2 overexpression abrogates hypoxia-mediated protective effect on ErbB2-expressing cells treated with lapatinib. All these data suggests that targeting MEK-Erk signaling pathway may reverse hypoxia mediated lapatinib resistance and might be a viable option for lapatinib resistant ErbB2-posive tumors. Indeed, a combination of lapatinib and an FDA approved MEK inhibitor trametinib abrogates hypoxia protective effect on cell growth inhibition and apoptosis in three dimensional (3D) cultures. Thus targeting MEK/ERK pathway in hypoxic breast cancer may improve an anti-ErbB2 therapy in breast cancer. Citation Format: Sergey Karakashev, Mauricio Reginato. Targeting Mek-Erk pathway abrogates hypoxia-mediated lapatinib resistance in ErbB2-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 716. doi:10.1158/1538-7445.AM2015-716
702. Long Term Metabolic Correction of Wilson Disease
Authors: Oihana Murillo, Daniel Moreno-Luqui, Cristina Gazquez, Debora Martínez-Espartosa, Ignacio Monreal, Laura Guembe, Armando Moreno, Fernando Corrales, Jesús Prieto, Ruben Hernández-Alcoceba, Gloria González-Aseguinolaza
Journal: Molecular Therapy (2015)

Wilson disease (WD) is an autosomal recessively inherited copper storage disorder due to mutations in the ATP7B gene resulting in impaired biliary copper excretion and hepatic copper accumulation. The increased hepatic copper concentration causes hepatocellular injury of variable intensity from acute liver failure to chronic hepatitis evolving to cirrhosis. Most often the first manifestation of the disorder is the hepatic disease which may be followed by copper deposition in the brain with resulting neurological damage. Current treatments are based on copper chelators that promote urinary excretion of the metal. These therapies should be maintained lifelong, may cause side effects and do not restore normal copper metabolism. In this work we assessed the efficacy of gene therapy to treat this condition. We transduced the liver of Atp7b-/- mice (a model of WD) with an adeno-associated vector serotype 8 (AAV8) encoding the human ATP7B cDNA placed under the control of the liver-specific a1-antitripsin promoter. After vector administration we performed serial determinations of serum transaminases, serum holoceruloplasmin concentration and ferroxidase activity and urinary copper excretion. In addition we assessed liver cooper concentration, oxidative status of hepatic proteins and histological liver damage in samples obtained at 6 months after therapy. We observed a dose-dependent therapeutic effect manifested by the reduction of transaminasemia and urinary copper excretion and normalization of serum holoceruloplasmin. Furthermore, we documented complete reversal of all hepatic alterations, including copper content, histopathological changes and protein oxidation. Conclusion: our data demonstrate that gene therapy provides long term correction of WD in a clinically relevant animal model of this disorder.
Abstract 698: CPI-based Crizotinib systemic study on discovery of phenotypic off-target
Authors: Jiazhi Sun, Lun Yang, Minghua Li, Shimin Zhang, Ian E. Heller, Johnathan Samuelson, Steven Cindric, Kunal Mishra, Eslam Mohamed, Feng Cheng, Kevin B. Sneed, Lin He, Shu-Feng Zhou
Journal: Cancer Research (2015)

Abstract Crizotinib, a first ever ALK/MET multi-targeted receptor tyrosine kinase inhibitor for the treatment of ALK-rearranged NSCLC patients. We hypothesize that crizotinib acts on other molecular targets in addition to tyrosine kinases ALK/MET and may play critical role given that there is a complex network of kinases that work together to regulate a number of important cellular processes and different disease signature. Approaching with a comprehensive docking method with our established chemical-protein interactome (CPI) and crizotinib, we have discovered 301 PDB-deposited proteins corresponding to 353 ligand binding pockets among a total of 1,780 PDB-deposited human protein entries. Systemic pharmacology approach also applied including validation the molecular target(s) of TKIs in vitro. Especially multiple human cellular models (including NSCLC and melanoma) and signaling study, luc-reporter, autophagy/apoptosis, proteomics study and NGS analysis applied. Interestingly, crizotinib besides had a high CPI binding score (ZZ_score) of -2.2778 against tyrosine kinase Lck, also had -1.4672, -1.1242, -0.7033 and -1.5384 against MAPK3, S6K, GSK-3β and HDAC 7A, respectively, which indicated crizotinib had potential broad range interaction with both TK and ser/thr kinases. Our data have showed that the crizotinib induced autophagy by activated LC3 in vitro and inhibited oncogenic Akt/mTOR signaling in human multiple melanoma cells resulting in G2/M cell cycle arrest. Furthermore, crizotinib increased p21Waf1/cip1 and Foxo3A expression and tumor suppressor miR-146a in human melanoma cells. Taken together, crizotinib induces miR-146a, autophagy and p21waf1/cip1 may potentially treat other type of human cancer by concurrently targeting tyrosine kinase, Akt/mTOR/Foxo axis and nuclear receptor, shedding a light for future both anti-cancer and anti-metabolic disorder drug discovery and development. This is the first CPI-based systemic study on leading discovery of crizotinib off-target phenotypic importance. These findings suggest that non-tyrosine kinase target of crizotinib may play critical role(s) for drug repositioning may represent a new and effective approach to expanding the application of existing drugs. Citation Format: Jiazhi Sun, Lun Yang, Minghua Li, Shimin Zhang, Ian E. Heller, Johnathan Samuelson, Steven Cindric, Kunal Mishra, Eslam Mohamed, Feng Cheng, Kevin B. Sneed, Lin He, Shu-Feng Zhou. CPI-based Crizotinib systemic study on discovery of phenotypic off-target. [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 698. doi:10.1158/1538-7445.AM2015-698
Systematic review is the highest level of evidence for knee osteoarthritis injection options, not expert society guidelines
Authors: John W Orchard
Journal: British Journal of Sports Medicine (2016)

It was pleasing to read the BMJ -reprinted article of Buchbinder et al 1 in the BJSM . Key recommendations from the article1 which are consistent with systematic review (SR) evidence include that knee arthroscopy is not superior to less invasive treatment for knee osteoarthritis (OA) (or degenerative meniscal tear); that degenerative meniscal tears are common in asymptomatic knees in the middle-aged and elderly; and that moderate level exercise is an effective treatment for knee OA.

Based on expert society guidelines only2 (not SRs), the authors make recommendations …
Blastic Plasmacytoid Dendritic Cell Neoplasm: Clinical, Immunohistochemical and Molecular Evaluation of 23 Cases with Primary Cutaneous Involvement,
Authors: Emilio Berti, Marco Lucioni, Francesco Onida, Francesca Novara, Elisabetta Caprini, Giacomo Fiandrino, Roberta Riboni, Daniele Fanoni, Pamela Vezzoli, Mariarosa Arra, Luigia Venegoni, Marta Nicola, Elena Dallera, Luca Arcaini, Giorgia Saporiti, Erica Travaglino, Emanuela Boveri, Orsetta Zuffardi, Giandomenico Russo, Marco Paulli
Journal: Blood (2011)
Three Novel Clonal Non-Characteristic Chromosome Aberrations in Acute Myeloid Leukemia Resembling Acute Promyelocytic Leukemia
Authors: Hongxing Liu, Wenjun Tian, Fang Wang, Juan Zhu, Wen Teng, Hui Wang, Tong Wang, Ping Wu, Ping Zhu, Tong Wu, Chunrong Tong
Journal: Blood (2011)
Abstract 2412: Assessment of clinical applications of circulating tumor DNA using an enhanced TAm-Seq platform
Authors: Andrew RJ Lawson, Vincent Plagnol, Abdelaziz Fahem, Tim Forshew, James D. Brenton, Davina Gale, Nitzan Rosenfeld
Journal: Cancer Research (2015)

Abstract Novel biomarkers are required to assess tumor burden and response in cancer as conventional biopsies are invasive, costly and only provide a snapshot of the mutational profile at a given time and location. A promising biomarker is the detection of genomic material released from tumors into the blood plasma of patients, known as circulating tumor DNA (ctDNA). ctDNA has been detected in plasma for a wide range of solid tumors and can be distinguished from other (germline) cell-free DNA by the presence of tumor-specific DNA alterations or known hotspot mutations. However, the potential of ctDNA as a biomarker has not yet been fully realized due to technical challenges associated with its detection and analysis, including the short fragment sizes (140-170 bp), small number of amplifiable copies and low/variable allele fractions of ctDNA. We have developed an enhanced platform for tagged-amplicon deep sequencing (TAm-Seq™). Using a combination of improved library preparation and bespoke data analysis methods, this platform can be used to sequence established cancer hotspots and the entire coding regions of selected genes, while preserving high levels of specificity and sensitivity. Using this approach, we have developed an assay that analyzes ∼20 kb of the genome (including regions of interest in more than 30 genes) with sensitivity down to a few mutant copies. Performance of this assay has been demonstrated using spike-in experiments, dilution series and clinical sample cohorts. Proof of concept studies have shown the potential of ctDNA to be used to assess tumor mutation status, monitor tumor dynamics, assess response to treatment and identify mutations associated with acquired drug resistance and disease progression. This non-invasive approach - a “liquid biopsy” - offers a revolution in how cancer can be detected, monitored and treated. Citation Format: Andrew RJ Lawson, Vincent Plagnol, Abdelaziz Fahem, Tim Forshew, James D. Brenton, Davina Gale, Nitzan Rosenfeld. Assessment of clinical applications of circulating tumor DNA using an enhanced TAm-Seq platform. [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 2412. doi:10.1158/1538-7445.AM2015-2412
Dysregulation of Interleukin (IL)-18 Gene Expression and Protein Production in Basal and Activated Cord Blood (CB) vs. Peripheral Blood (PB) Mononuclear Cells and Differential Effects of IL-18 in CB vs. PB T and NK Cell Immunity.
Authors: Prakash Satwani, Janet Ayello, Lynn Simpson, Carmella van de Ven, Mitchell S. Cairo
Journal: Blood (2004)