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https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#1
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27902604/the-use-of-delta-neutrophil-index-and-myeloperoxidase-index-as-diagnostic-predictors-of-strangulated-mechanical-bowel-obstruction-in-the-emergency-department
#2
Yong Sung Cha, Kang Hyun Lee, Jong Wook Lee, Eun Hee Choi, Hyung Il Kim, Oh Hyun Kim, Kyoung Chul Cha, Hyun Kim, Sung Oh Hwang
Early detection of bowel strangulation is difficult in patients with mechanical bowel obstruction (MBO). There have been no previous reports of predicting strangulation in MBO cases using the delta neutrophil index (DNI), which is a measure of the proportion of circulating immature granulocytes, or the myeloperoxidase index (MPXI), which is a measure of serum myeloperoxidase level. Therefore, we evaluated differences in initial DNI and MPXI upon presentation at the emergency department (ED) according to strangulation presence in MBO patients...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27892637/distribution-of-follicles-in-canine-ovarian-tissues-and-xenotransplantation-of-cryopreserved-ovarian-tissues-with-even-distribution-of-follicles
#3
I Wakasa, M Hayashi, Y Abe, H Suzuki
Ovarian follicles are not homogeneously distributed within the ovarian cortex in several species of mammals. Yet to maximize the reproducibility of experimental results of ovarian transplantation, it is essential to assess the degree of density and distribution of follicles in ovarian tissues before their transplantation. In this study, the ovarian cortex from 13 immature bitches (ten purebred and three mongrels) was sectioned into 1.0- to 1.5-mm(3) cubes, those were fixed, sectioned and stained with haematoxylin and eosin...
November 28, 2016: Reproduction in Domestic Animals, Zuchthygiene
https://www.readbyqxmd.com/read/27890379/synthesis-characterization-and-antineoplastic-activity-of-bis-aziridinyl-dimeric-naphthoquinone-a-novel-class-of-compounds-with-potent-activity-against-acute-myeloid-leukemia-cells
#4
Brandon A Carter-Cooper, Steven Fletcher, Dana Ferraris, Eun Yong Choi, Dahlia Kronfli, Smaraki Dash, Phuc Truong, Edward A Sausville, Rena G Lapidus, Ashkan Emadi
The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported...
November 17, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882356/intra-osseous-co-transplantation-of-cd34-selected-umbilical-cord-blood-and-mesenchymal-stromal-cells
#5
Leland Metheny, Saada Eid, Karen Lingas, Jane Reese, Howard Meyerson, Alexander Tong, Marcos de Lima, Alex Y Huang
Human mesenchymal stromal cells (MSC) have been shown to support the growth and differentiation of hematopoietic stem cells (HSC). We hypothesized that intra-osseous (IO) co-transplantation of MSC and umbilical cord blood (UCB) may be effective in improving early HSC engraftment, as IO transplantation has been demonstrated to enhance UCB engraftment in NOD SCID-gamma (NSG) mice. Following non-lethal irradiation (300rads), 6 groups of NSG mice were studied: 1) intravenous (IV) UCB CD34(+) cells, 2) IV UCB CD34(+) cells and MSC, 3) IO UCB CD34(+) cells, 4) IO UCB CD34(+) cells and IO MSC, 5) IO UCB CD34(+) cells and IV MSC, and 6) IV UCB CD34(+) and IO MSC...
2016: Hematol Med Oncol
https://www.readbyqxmd.com/read/27872864/f4-80-host-macrophages-are-a-barrier-to-murine-embryonic-stem-cell-derived-hematopoietic-progenitor-engraftment-in-vivo
#6
Heather L Thompson, Nico van Rooijen, Bryce T McLelland, Jennifer O Manilay
Understanding how embryonic stem cells and their derivatives interact with the adult host immune system is critical to developing their therapeutic potential. Murine embryonic stem cell-derived hematopoietic progenitors (ESHPs) were generated via coculture with the bone marrow stromal cell line, OP9, and then transplanted into NOD.SCID.Common Gamma Chain (NSG) knockout mice, which lack B, T, and natural killer cells. Compared to control mice transplanted with adult lineage-negative bone marrow (Lin(-) BM) progenitors, ESHP-transplanted mice attained a low but significant level of donor hematopoietic chimerism...
2016: Journal of Immunology Research
https://www.readbyqxmd.com/read/27859428/low-p16-ink4a-expression-in-early-passage-human-prostate-basal-epithelial-cells-enables-immortalization-by-telomerase-expression-alone
#7
Mindy Kim Graham, Lorenzo Principessa, Lizamma Antony, Alan K Meeker, John T Isaacs
BACKGROUND: There are two principal senescence barriers that must be overcome to successfully immortalize primary human epithelial cells in culture, stress-induced senescence, and replicative senescence. The p16(INK4a) /retinoblastoma protein (p16/Rb) pathway mediates stress-induced senescence, and is generally upregulated by primary epithelial cells in response to the artificial conditions from tissue culture. Replicative senescence is associated with telomere loss. Following each round of cell division, telomeres progressively shorten...
November 8, 2016: Prostate
https://www.readbyqxmd.com/read/27856463/ccl-2-is-a-kit-d816v-dependent-modulator-of-the-bone-marrow-microenvironment-in-systemic-mastocytosis
#8
Georg Greiner, Nadine Witzeneder, Angelika Berger, Klaus Schmetterer, Gregor Eisenwort, Ana-Iris Schiefer, Simone Roos, Theresia Popow-Kraupp, Leonhard Müllauer, Johannes Zuber, Veronika Sexl, Lukas Kenner, Wolfgang R Sperr, Peter Valent, Matthias Mayerhofer, Gregor Hoermann
Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. Similar to other myeloproliferative neoplasms, increased production of pro-fibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, only little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the pro-angiogenic cytokine CCL-2 in neoplastic mast cells...
November 16, 2016: Blood
https://www.readbyqxmd.com/read/27846885/autophagy-is-associated-with-chemoresistance-in-neuroblastoma
#9
Assila Belounis, Carine Nyalendo, Roxane Le Gall, Tina V Imbriglio, Mohamed Mahma, Pierre Teira, Mona Beaunoyer, Sonia Cournoyer, Elie Haddad, Gilles Vassal, Hervé Sartelet
BACKGROUND: Neuroblastoma (NB) is a frequent pediatric tumor characterized by a poor prognosis where a majority of tumors progress despite intensive multimodality treatments. Autophagy, a self-degradative process in cells, could be induced by chemotherapy and be associated with chemoresistance. The aim of this study was to determine whether: 1) autophagy is present in NB, 2) chemotherapy modified its levels, and 3) its inhibition decreased chemoresistance. METHODS: Immunohistochemical stainings were performed on samples from 184 NB patients in order to verify the expression of LC3B, a specific marker for autophagy, and Beclin 1, a positive regulator of autophagy...
November 15, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27827995/nod-scid-gamma-mice-are-permissive-to-allogeneic-hsc-transplantation-without-prior-conditioning
#10
Tom Verbiest, Rosemary Finnon, Natalie Brown, Paul Finnon, Simon Bouffler, Christophe Badie
Scid hematopoietic stem cells (HSCs) have an intrinsic defect in their maintenance within the bone marrow (BM) niche which facilitates HSC transplantation without the absolute requirement of prior conditioning. Nevertheless, NOD scid mice have a significantly altered life span due to early development of thymic lymphomas, which compromises the ability to study the long-term fate of exogenous HSCs and their progeny. Here, we present data on the transplantation of HSCs into NOD scid gamma (NSG) mice to achieve long-term engraftment without prior conditioning...
November 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27825124/acid-ceramidase-is-upregulated-in-aml-and-represents-a-novel-therapeutic-target
#11
Su-Fern Tan, Xin Liu, Todd E Fox, Brian M Barth, Arati Sharma, Stephen D Turner, Andy Awwad, Alden Dewey, Kenichiro Doi, Barbara Spitzer, Mithun Vinod Shah, Samy A F Morad, Dhimant Desai, Shantu Amin, Junjia Zhu, Jason Liao, Jong Yun, Mark Kester, David F Claxton, Hong-Gang Wang, Myles C Cabot, Edward H Schuchman, Ross L Levine, David J Feith, Thomas P Loughran
There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27804947/-necrotizing-sarcoid-granulomatosis
#12
L A Semenova, S G Radenska-Lopovok, S A Burtseva, Yu S Berezovsky, L N Lepekha
Necrotizing sarcoid granulomatosis (NSG) belongs to productive small-vessel vasculitis with the formation of sarcoid-like granulomas, which is accompanied by ischemic necrosis of varying degrees and duration. The disease involves the lung only. The clinical symptoms of the disease are nonspecific so the latter is detected rather rarely. The main diagnostic technique is morphological examination. Immune complex inflammation develops in the vessel walls with the formation of macrophage-histiocytic granulomas that do not contain epithelioid cells...
2016: Arkhiv Patologii
https://www.readbyqxmd.com/read/27803044/pre-clinical-evaluation-of-chimeric-antigen-receptors-targeting-cd70-expressing-cancers
#13
Qiong J Wang, Zhiya Yu, Ken-Ichi Hanada, Krishna Patel, David Kleiner, Nicholas P Restifo, James Yang
PURPOSE: CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate "on-target, off-tumor" toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70. EXPERIMENTAL DESIGN: Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different co-stimulatory domains from CD28 and/or 41BB were constructed...
November 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27801602/a-potent-adjuvant-effect-of-a-cd1d-binding-nkt-cell-ligand-in-human-immune-system-mice
#14
Xiangming Li, Jing Huang, Izumi Kaneko, Min Zhang, Shiroh Iwanaga, Masao Yuda, Moriya Tsuji
OBJECTIVES: A CD1d-binding invariant natural killer T (iNKT)-cell stimulatory glycolipid, namely 7DW8-5, is shown to enhance the efficacy of radiation-attenuated sporozoites (RAS)-based malaria vaccine in mice. In the current study, we aim to determine whether 7DW8-5 can display a potent adjuvant effect in human immune system (HIS) mice. METHODS: HIS-A2/hCD1d mice, which possess both functional human iNKT cells and CD8+ T cells, were generated by the transduction of NSG mice with adeno-associated virus serotype 9 expressing genes that encode human CD1d molecules and HLA-A*0201, followed by the engraftment of human hematopoietic stem cells...
November 16, 2016: Expert Review of Vaccines
https://www.readbyqxmd.com/read/27798825/biodistribution-of-self-assembling-polymer-gemcitabine-conjugate-after-systemic-administration-into-orthotopic-pancreatic-tumor-bearing-mice
#15
Krishna Kattel, Goutam Mondal, Feng Lin, Virender Kumar, Ram I Mahato
Therapeutic efficacy of gemcitabine (GEM) is severely limited due to its rapid metabolism by enzymatic deamination in vivo. We recently determined its therapeutic efficacy before (F-GEM) and after conjugation to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (mPEG-b-PCC-g-GEM-g-DC, abbreviated as P-GEM) in subcutaneous and orthotopic pancreatic tumor bearing mice. In this study, pharmacokinetic (PK) parameters and biodistribution profiles of F-GEM and P-GEM were determined after intravenous injection into orthotopic pancreatic tumor bearing NSG mice...
October 31, 2016: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27791035/mirna92a-targets-klf2-and-the-phosphatase-pten-signaling-to-promote-human-t-follicular-helper-precursors-in-t1d-islet-autoimmunity
#16
Isabelle Serr, Rainer W Fürst, Verena B Ott, Martin G Scherm, Alexei Nikolaev, Füsun Gökmen, Stefanie Kälin, Stephanie Zillmer, Melanie Bunk, Benno Weigmann, Nicole Kunschke, Brigitta Loretz, Claus-Michael Lehr, Benedikt Kirchner, Bettina Haase, Michael Pfaffl, Ari Waisman, Richard A Willis, Anette-G Ziegler, Carolin Daniel
Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)(+)CD4(+) TFH precursor phenotype...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27786411/hes4-a-potential-prognostic-biomarker-for-newly-diagnosed-patients-with-high-grade-osteosarcoma
#17
Madonna McManus, Eugenie Kleinerman, Yanwen Yang, John Andrew Livingston, Jared Mortus, Rocio Rivera, Patrick Zweidler-McKay, Keri Schadler
BACKGROUND: Prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis are lacking. Necrotic response of OS to preoperative chemotherapy correlates with survival and is determined 3-4 months after diagnosis. The purpose of this study is to identify biomarkers that will stratify patients into good or poor responders to chemotherapy at diagnosis and determine the role of potential biomarkers in OS pathogenesis. PROCEDURE: Because OS may be caused by disruptions of osteogenic differentiation, and the Notch pathway is one regulator of bone development, we examined the link between Notch effectors, OS differentiation, and OS outcome...
October 27, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27780867/interferon-%C3%AE-promotes-antibody-mediated-fratricide-of-acute-myeloid-leukemia-cells
#18
Kavin Fatehchand, Elizabeth L McMichael, Brenda F Reader, Huiqing Fang, Ramasamy Santhanam, Shalini Gautam, Saranya Elavazhagan, Payal Mehta, Nathaniel J Buteyn, Giovanna Merchand-Reyes, Sumithira Vasu, Xiaokui Mo, Don M Benson, James S Blachly, William E Carson, John C Byrd, Jonathan P Butchar, Susheela Tridandapani
Acute Myeloid Leukemia (AML) is characterized by the proliferation of immature myeloid-lineage blasts. Due to its heterogeneity and to the high rate of acquired drug resistance and relapse, new treatment strategies are needed. Here, we demonstrate that IFNγ promotes AML blasts to act as effector cells within the context of antibody therapy. Treatment with IFNγ drove AML blasts toward a more differentiated state, wherein they showed increased expression of the M1-related markers HLA-DR and CD86, as well as of FcγRI, which mediates effector responses to therapeutic antibodies...
October 25, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27778242/surgical-margins-for-duodenopancreatectomy
#19
R Coppola, M Cartillone, D Borzomati, G Nappo, S Valeri, T Petitti, G Perrone
Microscopic residual tumor (R1) affects prognosis of resected pancreatic head cancer patients. Surgeon's ability, caseload and accuracy of pathological staging affect the rate of R1 resections. The goal of this study was to verify if a standardized histopathological workup of the specimen affects the rate of microscopic residual tumor after PD for cancer. Two groups of specimens were managed with (Group 1, Standardized Group, SG) or without (Group 2, Non Standardized Group, NSG) a standardized histopathological workup reported by the Royal College of Pathologists...
September 2016: Updates in Surgery
https://www.readbyqxmd.com/read/27765906/targeted-ngs-array-cgh-and-patient-derived-tumor-xenografts-for-precision-medicine-in-advanced-breast-cancer-a-single-center-prospective-study
#20
Anthony Gonçalves, François Bertucci, Arnaud Guille, Severine Garnier, José Adelaide, Nadine Carbuccia, Oliver Cabaud, Pascal Finetti, Serge Brunelle, Gilles Piana, Jeanne Tomassin-Piana, Maria Paciencia, Eric Lambaudie, Cornel Popovici, Renaud Sabatier, Carole Tarpin, Magali Provansal, Jean-Marc Extra, François Eisinger, Hagay Sobol, Patrice Viens, Marc Lopez, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Max Chaffanet, Daniel Birnbaum
BACKGROUND: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population. RESULTS: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%)...
October 18, 2016: Oncotarget
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