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https://www.readbyqxmd.com/read/29316737/the-effect-of-lipopolysaccharide-on-noxa-expression-is-mediated-through-irf-1-3-and-7
#1
Sujan Piya, Tae-Hyoung Kim
Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, elicits the secretion of cytokines, such as interferons, that stimulate the host defense system. Previously, we demonstrated that interferons induce interferon regulatory factors (IRFs) 1, 3, and 7 that regulate transcription of Noxa and alter expression profiles of Bcl-2 family proteins in tumors. However, the immediate consequences of LPS stimulation on Noxa and BH3 expression in tumor cells remain uncharacterized. Here, we determined that LPS induced Noxa expression in CT26 cells...
January 11, 2018: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29298347/predicting-effective-pro-apoptotic-anti-leukaemic-drug-combinations-using-co-operative-dynamic-bh3-profiling
#2
Martin Grundy, Claire Seedhouse, Thomas Jones, Liban Elmi, Michael Hall, Adam Graham, Nigel Russell, Monica Pallis
The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide...
2018: PloS One
https://www.readbyqxmd.com/read/29237758/targeted-apoptosis-of-myofibroblasts-with-the-bh3-mimetic-abt-263-reverses-established-fibrosis
#3
David Lagares, Alba Santos, Paula E Grasberger, Fei Liu, Clemens K Probst, Rod A Rahimi, Norihiko Sakai, Tobias Kuehl, Jeremy Ryan, Patrick Bhola, Joan Montero, Mohit Kapoor, Murray Baron, Xaralabos Varelas, Daniel J Tschumperlin, Anthony Letai, Andrew M Tager
Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells...
December 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29229991/bok-promotes-chemical-induced-hepatocarcinogenesis-in-mice
#4
Tatiana Rabachini, Yuniel Fernandez-Marrero, Matteo Montani, Giulio Loforese, Valentina Sladky, Zhaoyue He, Daniel Bachmann, Simone Wicki, Andreas Villunger, Deborah Stroka, Thomas Kaufmann
BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK mRNA and protein in the liver...
December 11, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29077093/why-do-bcl-2-inhibitors-work-and-where-should-we-use-them-in-the-clinic
#5
REVIEW
Joan Montero, Antony Letai
Intrinsic apoptosis is controlled by the BCL-2 family of proteins but the complexity of intra-family interactions makes it challenging to predict cell fate via standard molecular biology techniques. We discuss BCL-2 family regulation and how to determine cells' readiness for apoptosis and anti-apoptotic dependence. Cancer cells often adopt anti-apoptotic defense mechanisms in response to oncogenic stress or anti-cancer therapy. However, by determining their anti-apoptotic addiction, we can use novel BH3 mimetics to overwhelm this apoptotic blockade...
October 27, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28960205/coordinated-repression-of-bim-and-puma-by-epstein-barr-virus-latent-genes-maintains-the-survival-of-burkitt-lymphoma-cells
#6
Leah Fitzsimmons, Andrew J Boyce, Wenbin Wei, Catherine Chang, Deborah Croom-Carter, Rosemary J Tierney, Marco J Herold, Andrew I Bell, Andreas Strasser, Gemma L Kelly, Martin Rowe
While the association of Epstein-Barr virus (EBV) with Burkitt lymphoma (BL) has long been recognised, the precise role of the virus in BL pathogenesis is not fully resolved. EBV can be lost spontaneously from some BL cell lines, and these EBV-loss lymphoma cells reportedly have a survival disadvantage. Here we have generated an extensive panel of EBV-loss clones from multiple BL backgrounds and examined their phenotype comparing them to their isogenic EBV-positive counterparts. We report that, while loss of EBV from BL cells is rare, it is consistently associated with an enhanced predisposition to undergo apoptosis and reduced tumorigenicity in vivo...
September 29, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28844952/targeting-cholangiocarcinoma
#7
REVIEW
Joachim C Mertens, Sumera Rizvi, Gregory J Gores
Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA...
August 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28804127/discovery-of-novel-drug-sensitivities-in-t-pll-by-high-throughput-ex-vivo-drug-testing-and-mutation-profiling
#8
E I Andersson, S Pützer, B Yadav, O Dufva, S Khan, L He, L Sellner, A Schrader, G Crispatzu, M Oleś, H Zhang, S Adnan-Awad, S Lagström, D Bellanger, J P Mpindi, S Eldfors, T Pemovska, P Pietarinen, A Lauhio, K Tomska, C Cuesta-Mateos, E Faber, S Koschmieder, T H Brümmendorf, S Kytölä, E-R Savolainen, T Siitonen, P Ellonen, O Kallioniemi, K Wennerberg, W Ding, M-H Stern, W Huber, S Anders, J Tang, T Aittokallio, T Zenz, M Herling, S Mustjoki
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles...
August 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28802908/apoptosis-signaling-and-bcl-2-pathways-provide-opportunities-for-novel-targeted-therapeutic-strategies-in-hematologic-malignances
#9
REVIEW
Huanling Wu, L Jeffrey Medeiros, Ken H Young
Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events...
August 8, 2017: Blood Reviews
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#10
REVIEW
Kiran Naqvi, Marina Konopleva, Farhad Ravandi
Acute myeloid leukemia (AML) remains a therapeutic challenge. Despite ongoing research, the standard therapy for AML has not changed significantly in the past four decades. With the identification of cytogenetic and molecular abnormalities, several promising therapeutic agents are currently being investigated. FLT3 mutation is a well-recognized target seen in 30% of the cytogenetically normal AML. More recently, the BCL2 family of anti-apoptotic proteins have also generated great interest as a therapeutic target...
October 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28737741/rapidly-inducible-cas9-and-dsb-ddpcr-to-probe-editing-kinetics
#11
John C Rose, Jason J Stephany, William J Valente, Bridget M Trevillian, Ha V Dang, Jason H Bielas, Dustin J Maly, Douglas M Fowler
We developed a chemically inducible Cas9 (ciCas9) and a droplet digital PCR assay for double-strand breaks (DSB-ddPCR) to investigate the kinetics of Cas9-mediated generation and repair of DSBs in cells. ciCas9 is a rapidly activated, single-component Cas9 variant engineered by replacing the protein's REC2 domain with the BCL-xL protein and fusing an interacting BH3 peptide to the C terminus. ciCas9 can be tunably activated by a compound that disrupts the BCL-xL-BH3 interaction within minutes. DSB-ddPCR demonstrates time-resolved, highly quantitative, and targeted measurement of DSBs...
September 2017: Nature Methods
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#12
REVIEW
Matthew S Davids
The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease...
August 31, 2017: Blood
https://www.readbyqxmd.com/read/28594323/epistatic-mutations-in-puma-bh3-drive-an-alternate-binding-mode-to-potently-and-selectively-inhibit-anti-apoptotic-bfl-1
#13
Justin M Jenson, Jeremy A Ryan, Robert A Grant, Anthony Letai, Amy E Keating
Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs...
June 8, 2017: ELife
https://www.readbyqxmd.com/read/28525842/indole-coumarin-thiadiazole-hybrids-an-appraisal-of-their-mcf-7%C3%A2-cell-growth-inhibition-apoptotic-antimetastatic-and-computational-bcl-2-binding-potential
#14
Pooja R Kamath, Dhanya Sunil, Manu M Joseph, Abdul Ajees Abdul Salam, Sreelekha T T
Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells...
August 18, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28511583/deciphering-the-crucial-residues-involved-in-heterodimerization-of-bak-peptide-and-anti-apoptotic-proteins-for-apoptosis
#15
Parthiban Marimuthu, Kalaimathy Singaravelu
B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, functioning via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins...
June 2, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28469964/comprehensive-pharmacological-profiling-of-neurofibromatosis-cell-lines
#16
Jianman Guo, Michael R Grovola, Hong Xie, Grace E Coggins, Patrick Duggan, Rukhsana Hasan, Jiale Huang, Danny W Lin, Claire Song, Gabriela M Witek, Simon Berritt, David C Schultz, Jeffrey Field
Patients with Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are predisposed to tumors of the nervous system. NF1 patients predominantly develop neurofibromas, and Malignant Peripheral Nerve Sheath Tumors (MPNST) while NF2 patients develop schwannomas and meningiomas. Here we quantified the drug sensitivities of NF1 and NF2 tumor cell lines in a high throughput platform. The platform contained a comprehensive collection of inhibitors of MEK, RAF, RAS, farnesyl transferase, PAK and ERK, representative drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents recommended for treating MPNST, such as doxorubicin and etoposide...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28439883/an-update-for-richter-syndrome-new-directions-and-developments
#17
REVIEW
Toby A Eyre, Anna Schuh
High-grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy-resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics...
August 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28425914/epstein-barr-virus-ensures-b-cell-survival-by-uniquely-modulating-apoptosis-at-early-and-late-times-after-infection
#18
Alexander M Price, Joanne Dai, Quentin Bazot, Luv Patel, Pavel A Nikitin, Reza Djavadian, Peter S Winter, Cristina A Salinas, Ashley Perkins Barry, Kris C Wood, Eric C Johannsen, Anthony Letai, Martin J Allday, Micah A Luftig
Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection...
April 20, 2017: ELife
https://www.readbyqxmd.com/read/28401226/the-charge-transfer-limit-of-a-chemical-adduct-the-role-of-perturbation-on-external-potential
#19
Aabid Hamid, Atul Anand, Ram Kinkar Roy
Full profiles of the components (positive and negative) of density functional reactivity theory (DFRT) based stabilization energy with respect to the amount of charge transfer (ΔN) are investigated on three different Diels-Alder pairs and twelve different charge transfer complexes formed by BH3-NH3 and their derivatives. One interesting observation is that the stabilization energy is zero when the charge transfer (ΔN) is either zero (lower limit, L.L.) or two times (higher limit, H.L.) the charge transfer at equilibrium (i...
May 3, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28370955/supported-rhodium-catalysts-for-ammonia-borane-hydrolysis-dependence-of-the-catalytic-activity-on-the-highest-occupied-state-of-the-single-rhodium-atoms
#20
Liangbing Wang, Hongliang Li, Wenbo Zhang, Xiao Zhao, Jianxiang Qiu, Aowen Li, Xusheng Zheng, Zhenpeng Hu, Rui Si, Jie Zeng
Supported metal nanocrystals have exhibited remarkable catalytic performance in hydrogen generation reactions, which is influenced and even determined by their supports. Accordingly, it is of fundamental importance to determine the direct relationship between catalytic performance and metal-support interactions. Herein, we provide a quantitative profile for exploring metal-support interactions by considering the highest occupied state in single-atom catalysts. The catalyst studied consisted of isolated Rh atoms dispersed on the surface of VO2 nanorods...
March 30, 2017: Angewandte Chemie
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