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Panobinostat

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https://www.readbyqxmd.com/read/28415789/hmga2-translocation-induced-in-skin-tumorigenesis
#1
Yong Li, Xiang-Ying Pi, Kelsey Boland, Sonali Lad, Kelly Johnson, Catherine Verfaillie, Rebecca J Morris
Hmga2 protein, a transcription factor involved in chromatin architecture, is expressed chiefly during development, where it has many key biological functions. When expressed in adult tissues from in various organs, Hmga2 is always related to cancer development. The role of Hmga2 in skin tumorigenesis is, however, not yet understood. We demonstrated that Hmga2 can be found in non-transformed epidermis, specifically located to the membrane of keratinocytes (KCs) in epidermis. Ex vivo culture of KCs and development of skin carcinomas in DMBA and TPA mouse models was associated with translocation of the Hmga2 protein from the membrane into the nucleus, where Hmga2 induced its own expression by binding to the Hmga2 promoter...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28398261/novel-proteasome-inhibitors-and-histone-deacetylase-inhibitors-progress-in-myeloma-therapeutics
#2
REVIEW
Saurabh Chhabra
The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death...
April 11, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28388244/which-therapies-will-move-to-the-front-line-for-multiple-myeloma
#3
María J Cejalvo, Javier de la Rubia
Despite substantial progress, multiple myeloma (MM) remains an incurable disease. Recently the availability of several novel drugs with different and innovative mechanisms of action (daratumumab, elotuzumab, carfilzomib, ixazomib, and panobinostat) has increased the therapeutic options but has also increased complexity in the management of patients with MM. Areas covered: The outstanding results observed in the relapsed setting with regimens including these new drugs has provided the investigators with several treatment options that are being tested also in patients with newly diagnosed MM...
April 24, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28363998/e3-ligase-ciap2-mediates-downregulation-of-mre11-and-radiosensitization-in-response-to-hdac-inhibition-in-bladder-cancer
#4
Judith Nicholson, Sarah Jevons, Blaz Groselj, Sophie Ellermann, Rebecca Konietzny, Martin Kerr, Benedikt M Kessler, Anne E Kiltie
The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is post-translational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated...
March 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/28353192/three-cases-of-relapsed-refractory-multiple-myeloma-under-hemodialysis-treated-with-panobinostat-bortezomib-dexamethasone-fvd
#5
Yasunobu Sekiguchi, Haruko Takizawa, Tadaaki Inano, Yasutaka Fukuda, Mutsumi Wakabayashi, Keiji Sugimoto, Shigeki Tomita, Hiroshi Izumi, Noriko Nakamura, Tomohiro Sawada, Yasunori Ohta, Norio Komatsu, Masaaki Noguchi
Three patients under hemodialysis (HD) with relapsed/refractory multiple myeloma (MM) were administered panobinostat/bortezomib/dexamethasone (FVD). Case 1: The patient was a 66-year-old male with BJP-κ. FVD was effective, but HD could not be discontinued. He developed Grade 3 adverse events (AEs), including nausea, dehydration, and fatigue, following the common terminology criteria for adverse events v4.0. FVD was discontinued after the third course, while HD was continued. Case 2: The patient was a 65-year-old female with IgG-λ + BJP-λ...
March 28, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28352655/panobinostat-acts-synergistically-with-ibrutinib-in-diffuse-large-b-cell-lymphoma-cells-with-myd88-l265-mutations
#6
Patrizia Mondello, Elliott J Brea, Elisa De Stanchina, Eneda Toska, Aaron Y Chang, Myles Fennell, Venkatraman Seshan, Ralph Garippa, David A Scheinberg, José Baselga, Hans-Guido Wendel, Anas Younes
Diffuse large B cell lymphoma (DLBCL) frequently harbors genetic alterations that activate the B cell receptor (BCR) and TLR pathways, which converge to activate NF-κB. While selective inhibition of BTK with ibrutinib causes clinical responses in relapsed DLBCL patients, most responses are partial and of a short duration. Here, we demonstrated that MyD88 silencing enhanced ibrutinib efficacy in DLBCL cells harboring MyD88 L265P mutations. Chemical downregulation of MyD88 expression with HDAC inhibitors also synergized with ibrutinib...
March 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28347676/treating-multiple-myeloma-patients-with-oral-therapies
#7
REVIEW
Shaji K Kumar, Ravi Vij, Stephen J Noga, Deborah Berg, Lonnie Brent, Lawrence Dollar, Ajai Chari
Recent advances have highlighted the importance of long-term, continuous treatment in multiple myeloma (MM) to improve survival. However, treatment burden continues to negatively impact the real-world duration of MM therapy, and strategies to limit the adverse impact of treatment on patient quality of life are therefore particularly important. Oral MM therapies include the immunomodulatory drugs lenalidomide, thalidomide, and pomalidomide; the alkylating agents melphalan and cyclophosphamide; the histone deacetylase inhibitor panobinostat; the corticosteroids prednisone and dexamethasone; and the proteasome inhibitor ixazomib...
March 7, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28338993/dihydrocelastrol-inhibits-multiple-myeloma-cell-proliferation-and-promotes-apoptosis-through-erk1-2-and-il-6-stat3-pathways-in-vitro-and-in-vivo
#8
Liangning Hu, Huiqun Wu, Bo Li, Dongliang Song, Guang Yang, Gege Chen, Bingqian Xie, Zhijian Xu, Yong Zhang, Dandan Yu, Jun Hou, Wenqin Xiao, Xi Sun, Gaomei Chang, Yiwen Zhang, Lu Gao, Bojie Dai, Yi Tao, Jumei Shi, Weiliang Zhu
Multiple myeloma (MM) is the second most frequent malignant hematological disease. Dihydrocelastrol (DHCE) is synthesized by hydrogenated celastrol, a treterpene isolated from Chinese medicinal plant Tripterygium regelii. In this study, we first reported the anti-tumor activity of DHCE on MM cells. We found that DHCE could inhibit cell proliferation and promote apoptosis through caspase-dependent way in vitro. In addition, DHCE could inactivate the expression of interleukin (IL)-6 and downregulate the phosphorylation of extracellular regulated protein kinases (ERK1/2) and the signal transducer and activator of transcription 3 (STAT3) in MM...
March 17, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28325256/how-have-evolutions-in-strategies-for-the-treatment-of-relapsed-refractory-multiple-myeloma-translated-into-improved-outcomes-for-patients
#9
REVIEW
Pieter Sonneveld, Edwin De Wit, Philippe Moreau
Although multiple myeloma (MM) remains incurable, the introduction of novel agents has improved clinical outcomes dramatically over the past 15 years. Response rates have risen from ∼30% with single agents to up to 90% with combination therapies. The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, form the foundations for treatment of relapsed and/or refractory MM (RRMM). Newer agents, such as the IMiD pomalidomide, the histone deacetylase inhibitor panobinostat and the proteasome inhibitors carfilzomib and ixazomib, as well as the monoclonal antibodies daratumumab and elotuzumab, have further improved overall response rates in these patients...
April 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28273193/-drug-therapy-of-lymphomas
#10
Lajos Gergely
The therapy of lymphomas has undergone a major expansion during the last decade. Novel therapeutic targets have appeared beyond classical chemotherapeutic combinations. These novel drugs have very pronounced action across lymphoma types, and their toxicity profile is usually better tolerable compared to standard chemotherapies. These new therapies are enabling us to offer treatment to those patients who have refractory disease, and we had no option to treat them before these drugs. The author describes several new therapeutic options...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28260886/convection-enhanced-delivery-of-panobinostat-lbh589-loaded-pluronic-nano-micelles-prolongs-survival-in-the-f98-rat-glioma-model
#11
W G Singleton, A M Collins, A S Bienemann, C L Killick-Cole, H R Haynes, D J Asby, C P Butts, M J Wyatt, N U Barua, S S Gill
BACKGROUND: The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). MATERIALS AND METHODS: The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28249907/hdac-inhibitor-panobinostat-engages-host-innate-immune-defenses-to-promote-the-tumoricidal-effects-of-trastuzumab-in-her2-tumors
#12
Mikolaj Medon, Eva Vidacs, Stephin J Vervoort, Jason Li, Misty R Jenkins, Kelly M Ramsbottom, Joseph A Trapani, Mark J Smyth, Phillip K Darcy, Peter W Atadja, Michael A Henderson, Ricky W Johnstone, Nicole M Haynes
Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and non-autonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, co-treatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells...
March 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28205262/modern-multiple-myeloma-therapy-deep-sustained-treatment-response-and-good-clinical-outcomes
#13
REVIEW
O Landgren, K Iskander
In the USA at the beginning of this century, the average overall survival in patients with multiple myeloma was about 3 years. Around that time, three drugs (bortezomib, lenalidomide and thalidomide) were introduced for the treatment of multiple myeloma and, in 2012, carfilzomib received accelerated approval by the US Food and Drug Administration (FDA). Driven by access to better drugs, median overall survival in younger patients (aged <50 years) was >10 years by 2014. The FDA approved 14 new drugs for the treatment of cancer in 2015; four of these were approved for the treatment of myeloma (panobinostat, daratumumab, elotuzumab and ixazomib)...
February 16, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28203342/optimizing-current-and-emerging-therapies-in-multiple-myeloma-a-guide-for-the-hematologist
#14
REVIEW
Shahzad Raza, Rachael A Safyan, Evan Rosenbaum, Alex S Bowman, Suzanne Lentzsch
Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of end-organ damage...
February 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28202759/relationship-between-measures-of-hiv-reactivation-and-the-decline-of-latent-reservoir-under-latency-reversing-agents
#15
Janka Petravic, Thomas A Rasmussen, Sharon R Lewin, Stephen J Kent, Miles P Davenport
Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRA) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRA are explored in clinical trials, it becomes increasingly important to assess the effect of increased HIV reactivation rate on the decline of latently infected cells, and estimate LRA efficacy in increasing virus reactivation...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28193631/histone-deacetylase-inhibitors-correct-the-cholesterol-storage-defect-in-most-niemann-pick-c1-mutant-cells
#16
Nina H Pipalia, Kanagaraj Subramanian, Shu Mao, Harold Ralph, Darren M Hutt, Samantha M Scott, William E Balch, Frederick R Maxfield
Niemann-Pick C (NPC) disease is an autosomal recessive disorder that leads to excessive storage of cholesterol and other lipids in late endosomes and lysosomes. The large majority of NPC disease is caused by mutations in NPC1, a large polytopic membrane protein that functions in late endosomes. There are many disease-associated mutations in NPC1, and most patients are compound heterozygotes. The most common mutation, NPC1(I1061T), has been shown to cause endoplasmic reticulum-associated degradation of the NPC1 protein...
April 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28171800/epigenetic-drug-combination-overcomes-osteoblast-induced-chemoprotection-in-pediatric-acute-lymphoid-leukemia
#17
Anthony Quagliano, Anilkumar Gopalakrishnapillai, Sonali P Barwe
Although there has been much progress in the treatment of acute lymphoblastic leukemia (ALL), decreased sensitivity to chemotherapy remains a significant issue. Recent studies have shown how interactions with the bone marrow microenvironment can protect ALL cells from chemotherapy and allow for the persistence of the disease. Epigenetic drugs have been used for the treatment of ALL, but there are no reports on whether these drugs can overcome bone marrow-induced chemoprotection. Our study investigates the ability of the DNA methyltransferase inhibitor azacitidine and the histone deacetylase inhibitor panobinostat to overcome chemoprotective effects mediated by osteoblasts...
May 2017: Leukemia Research
https://www.readbyqxmd.com/read/28157715/combined-use-of-irinotecan-with-histone-deacetylase-inhibitor-belinostat-could-cause-severe-toxicity-by-inhibiting-sn-38-glucuronidation-via-ugt1a1
#18
Lingzhi Wang, Chong En Linus Chan, Andrea Li-Ann Wong, Fang Cheng Wong, Siew Woon Lim, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Lawrence Soon-U Lee, Ross Soo, Wei Peng Yong, Soo Chin Lee, Paul Chi-Lui Ho, Gautam Sethi, Boon Cher Goh
SN-38, the active metabolite of irinotecan, and histone deacetylase inhibitors (HDACis) such as belinostat, vorinostat and panobinostat, have all been shown to be deactivated by glucuronidation via UGTs. Since they all compete for UGTs for deactivation, we aimed to investigate the inhibitory effect of various HDACis on the glucuronidation of SN-38. This inhibitory effect was determined by measuring the formation rate of SN-38 glucuronide after SN-38 incubation with human recombinant UGT1A isoforms (1A1, 1A6, 1A7 and 1A9) and pooled human liver microsomes (HLM, wild type, UGT1A1*1*28 and UGT1A1*28*28 allelic variants), with and without HDACis...
February 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28151709/progress-and-paradigms-in-multiple-myeloma
#19
EDITORIAL
Kenneth C Anderson
Remarkable progress has been achieved in multiple myeloma, and patient median survival has been extended 3- to 4-fold. Specifically, there have been 18 newly approved treatments for multiple myeloma in the past 12 years, including seven in 2015, and the treatment paradigm and patient outcome have been transformed. The definition of patients benefitting from these therapies has been broadened. Response criteria now include minimal residual disease (MRD), assessed in bone marrow by multicolor flow cytometry or sequencing, and by imaging for extramedullary disease...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28132772/profiling-of-human-epigenetic-regulators-using-a-semi-automated-real-time-qpcr-platform-validated-by-next-generation-sequencing
#20
Amel Dudakovic, Martina Gluscevic, Christopher R Paradise, Halil Dudakovic, Farzaneh Khani, Roman Thaler, Farah S Ahmed, Xiaodong Li, Allan B Dietz, Gary S Stein, Martin A Montecino, David R Deyle, Jennifer J Westendorf, Andre J van Wijnen
Epigenetic mechanisms control phenotypic commitment of mesenchymal stromal/stem cells (MSCs) into osteogenic, chondrogenic or adipogenic lineages. To investigate enzymes and chromatin binding proteins controlling the epigenome, we developed a hybrid expression screening strategy that combines semi-automated real-time qPCR (RT-qPCR), next generation RNA sequencing (RNA-seq), and a novel data management application (FileMerge). This strategy was used to interrogate expression of a large cohort (n>300) of human epigenetic regulators (EpiRegs) that generate, interpret and/or edit the histone code...
April 20, 2017: Gene
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