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https://www.readbyqxmd.com/read/27932211/a-novel-class-of-somatic-mutations-in-blood-detected-preferentially-in-cd8-cells
#1
Miko Valori, Lilja Jansson, Anna Kiviharju, Pekka Ellonen, Hanna Rajala, Shady Adnan Awad, Satu Mustjoki, Pentti J Tienari
Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated...
December 5, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27923841/biological-and-clinical-relevance-of-associated-genomic-alterations-in-myd88-l265p-and-non-l265p-mutated-diffuse-large-b-cell-lymphoma-analysis-of-361-cases
#2
Sydney Dubois, Pierre-Julien Viailly, Elodie Bohers, Philippe Bertrand, Philippe Ruminy, Vinciane Marchand, Catherine Maingonnat, Sylvain Mareschal, Jean-Michel Picquenot, Dominique Penther, Jean-Philippe Jais, Bruno Tesson, Pauline Peyrouze, Martin Figeac, Fabienne Desmots, Thierry Fest, Corinne Haioun, Thierry Lamy, Christiane Copie-Bergman, Bettina Fabiani, Richard Delarue, Frederic Peyrade, Marc André, Nicolas Ketterer, Karen Leroy, Gilles Salles, Thierry J Molina, Herve Tilly, Fabrice Jardin
PURPOSE: MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of Activated B-Cell like (ABC) Diffuse Large B Cell Lymphoma (DLBCL), leading to constitutive NFkB pathway activation. The aim of this study was to examine the distinct genomic profiles of MYD88 mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants. EXPERIMENTAL DESIGN: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-type) was submitted to next generation sequencing (NGS) focusing on 34 genes in order to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses...
December 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27918558/quantitating-drug-target-engagement-in-single-cells-in-vitro-and-in-vivo
#3
J Matthew Dubach, Eunha Kim, Katherine Yang, Michael Cuccarese, Randy J Giedt, Labros G Meimetis, Claudio Vinegoni, Ralph Weissleder
Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target...
December 5, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27912175/structural-optimization-of-diphenylpyrimidine-derivatives-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-with-improved-activity-toward-b-leukemia-cell-lines
#4
Dan Zhao, Shanshan Huang, Menghua Qu, Changyuan Wang, Zhihao Liu, Zhen Li, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma, Xiaohong Shu
A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent BTK inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC50 values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib...
November 23, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27909342/ristocetin-induced-platelet-aggregation-for-monitoring-of-bleeding-tendency-in-cll-treated-with-ibrutinib
#5
L Kazianka, C Drucker, C Skrabs, W Thomas, T Melchardt, S Struve, M Bergmann, P B Staber, E Porpaczy, C Einberger, M Heinz, A Hauswirth, M Raderer, I Pabinger, R Thalhammer, A Egle, C-M Wendtner, G Follows, G Hoermann, P Quehenberger, B Jilma, U Jaeger
Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27908637/response-of-three-cyprinid-fish-species-to-the-scavenger-deterrent-factor-produced-by-the-mutualistic-bacteria-associated-with-entomopathogenic-nematodes
#6
Ramalingam Karthik Raja, Dilipkumar Aiswarya, Baris Gulcu, Manickam Raja, Pachiappan Perumal, Sivaperumal Sivaramakrishnan, Harry K Kaya, Selcuk Hazir
The symbiotic bacteria, Photorhabdus and Xenorhabdus associated with entomopathogenic nematodes (EPNs) in the genera Heterorhabditis and Steinernema, respectively, produce a compound(s) called the Scavenging Deterrent Factor (SDF). SDF deters a number of terrestrial insect scavengers and predators and one bird species from feeding on host insects killed by the nematode-bacterium complex but has not been tested against aquatic vertebrates. Moreover, the Heterorhabditis-Photorhabdus association is believed to have evolved in an aquatic environment...
November 29, 2016: Journal of Invertebrate Pathology
https://www.readbyqxmd.com/read/27904766/the-role-of-pim1-in-the-ibrutinib-resistant-abc-subtype-of-diffuse-large-b-cell-lymphoma
#7
Hsu-Ping Kuo, Scott A Ezell, Sidney Hsieh, Karl J Schweighofer, Leo Wk Cheung, Shiquan Wu, Mutiah Apatira, Mint Sirisawad, Karl Eckert, Yu Liang, Jeff Hsu, Chun-Te Chen, Darrin Beaupre, Betty Y Chang
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous lymphoma and the most common subtype of non-Hodgkin lymphoma, accounting for roughly 30% of newly diagnosed cases in the United States. DLBCL can be separated into the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, with distinct gene expression profiles, oncogenic aberrations, and clinical outcomes. ABC-DLBCL is characterized by chronically active B-cell receptor (BCR) signaling that can be modulated by Bruton's tyrosine kinase (BTK) activity...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27904138/cirmtuzumab-inhibits-wnt5a-induced-rac1-activation-in-chronic-lymphocytic-leukemia-treated-with-ibrutinib
#8
J Yu, L Chen, B Cui, C Wu, M Y Choi, Y Chen, L Zhang, L Z Rassenti, G F Widhopf, T J Kipps
Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival...
December 1, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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
#9
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/27899962/new-emerging-therapies-in-the-management-of-chronic-lymphocytic-leukemia
#10
Xiao-Lin Li, Ci-Xian Zhang
Chronic lymphocytic leukemia (CLL) is considered incurable despite advances in management strategies. New drugs targeting cell pathways are currently being developed for the efficient management of CLL. Various strategies involving different targets have been developed, or are currently in the developing stage. A search was conducted in the electronic database PubMed, for pre-clinical as well as clinically controlled trials reporting various strategies against CLL currently under investigation. Novel strategies included use of antibodies, small cell inhibitors, such as spleen tyrosine kinase, LYN, cyclin-dependent kinase, and histone deacetylase inhibitors...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27883180/mitochondrial-reactive-oxygen-species-suppress-humoral-immune-response-through-reduction-of-cd19-expression-in-b-cells-in-mice
#11
Masato Ogura, Takeshi Inoue, Junko Yamaki, Miwako K Homma, Tomohiro Kurosaki, Yoshimi Homma
Reactive oxygen species (ROS) are implicated in the modulation of diverse processes including immune responses. To evaluate the effects of metabolic ROS produced by mitochondria on B-cell function and development, we created transgenic (Tg) mice expressing a phosphorylation-defective mutant of succinate dehydrogenase A (SDHA(Y215F) ) in B cells (bSDHA(Y215F) ). Splenic B cells in male, but not female, bSDHA(Y215F) mice produced three times more ROS than those in the control mice, and had decreased production of IgM, IgG1 , and IgG3 , and affinity maturation of IgG1 against T-cell-dependent antigens...
November 24, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27879958/evaluation-of-a-6-year-old-multicentric-standard-endovascular-treatment-of-critical-limb-ischemia-in-the-drug-eluting-era
#12
Vincenzo Brizzi, Caroline Caradu, Xavier Berard, Gerard Sassoust, Dominique Midy, Eric Ducasse
BACKGROUND: There has been increasing evidence to support the endovascular- first approach in the treatment of below the knee (BTK) lesions. Plain Old Balloon Angioplasty (POBA), with bailout bare-metal stent scaffolding in case of flow limiting dissection or recoil, have been considered the standard treatment of choice but industries are continually developing innovative equipment and dedicated technologies, such as drug-eluting platforms whose use is increasingly extended, despite significant costs and lack of high-quality evidence to support a well- established strategy...
November 23, 2016: Journal of Cardiovascular Surgery
https://www.readbyqxmd.com/read/27867589/bruton-s-agammaglobulinemia-in-an-adult-male-due-to-a-novel-mutation-a-case-report
#13
Yuanda Xu, Qi Qing, Xuesong Liu, Sibei Chen, Ziyi Chen, Xuefeng Niu, Yaxia Tan, Weiqun He, Xiaoqing Liu, Yimin Li, Rongchang Chen, Ling Chen
X-linked agammaglobulinemia (XLA) is caused by mutation in the gene coding for Bruton's tyrosine kinase (BTK), which impairs peripheral B cell maturation and hypogammaglobulinemia. In this report, we present a case of XLA in a 22-year-old adult male. Genetic testing revealed a novel mutation located at the conserved region (c.383T>C). The patient had a history of recurrent respiratory tract infection which eventually progressed to chronic type II respiratory failure. Several pathogenic bacteria were isolated on culture of respiratory secretions obtained on bronchoscopy...
October 2016: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/27865897/enigmas-in-tumor-resistance-to-kinase-inhibitors-and-calculation-of-the-drug-resistance-index-for-cancer-dric
#14
REVIEW
C I Edvard Smith
Darwinian selection is also applicable when antibiotics, the immune system or other host factors shape the repertoire of microorganisms, and similarly, clonal selection is the hallmark of tumor evolution. The ongoing revolution in new anti-cancer treatment modalities, combined with an unprecedented precision in characterizing malignant clones at the level below one percent, profoundly improves the understanding of repertoire-tuning mechanisms. There is no fundamental difference between selection of the tumor cells in the presence, or absence, of therapy...
November 16, 2016: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/27854034/efficient-preparation-of-s-n-boc-3-hydroxylpiperidine-through-bioreduction-by-a-thermostable-aldo-ketoreductase
#15
Mengyan He, Shuo Zhou, Maolin Cui, Xiaolu Jin, Dunyue Lai, Shuangling Zhang, Zhiguo Wang, Zhenming Chen
(S)-N-Boc-3-hydroxypiperidine ((S)-NBHP) is a key pharmaceutical intermediate and the chiral source in synthesizing Imbruvica, which is a newly approved drug in lymphoma therapy by targeting Bruton's tyrosine kinase (BTK). Current chemical synthesis of (S)-NBHP suffered from the need of noble metal catalyst and low yield. The single reported bioconversion of (S)-NBHP was achieved by using recombinant ketoreductase, but enzyme sequence was kept confidential and the catalytic process suffered from the thermodeactivation and substrate inhibition...
November 16, 2016: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/27833403/predictors-for-better-blood-flow-restoration-of-long-segmental-below-the-knee-chronic-total-occlusions-after-endovascular-therapy-in-diabetic-patients
#16
Xiao-Li Song, Yue-Qi Zhu, Hai-Tao Lu, Fang Liu, Li-Ming Wei, Heoung Keun Kang, Jun-Gong Zhao
OBJECTIVE: To prospectively investigate predictors for good restoration of blood flow of below-the-knee (BTK) chronic total occlusions (CTOs) after endovascular therapy in diabetes mellitus (DM) patients. MATERIALS AND METHODS: A total of 120 long-segmental (≥ 5 cm) BTK, CTOs in 81 patients who underwent recanalization were included in this study. After angioplasty, blood-flow restoration was assessed using modified thrombolysis in myocardial ischemia grades and classified as good flow (grade 3) and poor flow (grade 1/2)...
November 2016: Korean Journal of Radiology: Official Journal of the Korean Radiological Society
https://www.readbyqxmd.com/read/27825467/future-therapeutic-options-for-patients-with-waldenstr%C3%A3-m-macroglobulinemia
#17
REVIEW
Jorge J Castillo, Zachary R Hunter, Guang Yang, Kimon Argyropoulos, M Lia Palomba, Steven P Treon
Waldenström macroglobulinemia (WM) is a rare lymphoma characterized by the accumulation of IgM-producing lymphoplasmacytic cells. Although WM patients can experience prolonged remissions, the disease invariably recurs. Therefore, novel treatments associated with higher success rates and lower toxicity profiles are needed. The discovery of recurrent mutations in the MYD88 and CXCR4 genes has unraveled potential therapeutic targets in WM patients. As a result of these findings and based on the design and execution of a prospective clinical trial, the FDA granted approval to ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, to treat patients with symptomatic WM...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27825466/current-therapy-guidelines-for-waldenstrom-s-macroglobulinaemia
#18
REVIEW
Efstathios Kastritis, Meletios A Dimopoulos
Waldenstrom's macroglobulinaemia (WM) is a B-cell neoplasm in which bone marrow is infiltrated by lymphoplasmacytic cells that secrete monoclonal immunoglobulin M (IgM). More than a decade ago, specific criteria were agreed to define diagnosis and symptomatic disease requiring therapy; however, treatment recommendations change as new options emerge. Treatment decisions consider specific disease characteristics (burden of disease, IgM levels, presence of cytopenias) and patient characteristics (age, comorbidities, toxicity)...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27825463/preclinical-models-of-waldenstr%C3%A3-m-s-macroglobulinemia-and-drug-resistance
#19
REVIEW
Sikander Ailawadhi, Aneel Paulus, Asher Chanan-Khan
Newer therapeutic strategies are emerging in Waldenström's Macroglobulinemia (WM), which has traditionally been an orphan disease diagnosis. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was FDA-approved in 2015 as the first ever drug for the treatment of WM. This being a targeted therapy, has given rise to increased research into novel agents and pathways that can be exploited for clinical benefit in WM. In order to understand the underlying mechanisms of disease behavior as well as to test the benefit of various drugs, appropriate preclinical models are required...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27825462/targeting-cell-adhesion-and-homing-as-strategy-to-cure-waldenstr%C3%A3-m-s-macroglobulinemia
#20
REVIEW
Steven T Pals, Marie José Kersten, Marcel Spaargaren
Most B-cell malignancies strictly depend on signals from the microenvironment for their survival and proliferation. This niche-dependency can be regarded as their Achilles' heel and provides an excellent target for therapy. Waldenström's macroglobulinemia (WM) is characterized by the accumulation of neoplastic post-germinal center B cells within the bone marrow (BM). Interestingly, one third of the patients carry activating mutations in the chemokine receptor CXCR4, a key mediator of B cell and plasma cell homing to the BM...
June 2016: Best Practice & Research. Clinical Haematology
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