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https://www.readbyqxmd.com/read/28212825/inhibition-of-ubiquitin-proteasome-function-prevents-monocrotaline-induced-pulmonary-arterial-remodeling
#1
Yanting Zhu, Yinxia Wu, Wenhua Shi, Jian Wang, Xin Yan, Qingting Wang, Ya Liu, Lan Yang, Li Gao, Manxiang Li
AIMS: Previous study has indicated that inhibition of proteasome function ameliorates the development of pulmonary arterial hypertension (PAH), while its underlying mechanisms are still unclear. This study was performed to address these issues. MATERIAL AND METHODS: Male Sprague-Dawley (SD) rats were divided into five groups: control group, PAH group, vehicle treated PAH group, MG-132 treated PAH group and bortezomib treated PAH group. PAH model was established by a single intraperitoneal injection of monocrotaline (MCT)...
February 14, 2017: Life Sciences
https://www.readbyqxmd.com/read/28211054/real-world-use-of-pomalidomide-and-dexamethasone-in-double-refractory-multiple-myeloma-suggests-benefit-in-renal-impairment-and-adverse-genetics-a-multi-centre-uk-experience
#2
Nicola Maciocia, Andrew Melville, Simon Cheesman, Faye Sharpley, Karthik Ramasamy, Matthew Streetly, Matthew Jenner, Reuben Benjamin, Steve Schey, Paul Maciocia, Rakesh Popat, Shirley D'sa, Ali Rismani, Aviva Cerner, Kwee Yong, Neil Rabin
Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40-89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment...
February 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28209043/-bortezomib-inhibits-hypoxia-induced-increase-of-orai-1-expression-in-pulmonary-arterial-smooth-muscle-cell
#3
L Xu, G Y Tian, L H Wang, Y B Liu, Z F Gao, G H Li, X H Fu
Objective: In this study, a primary culture system for the rat distal pulmonary arterial smooth muscle cell (PASMC) was established to observe the effect of Bortezomib a treatment on the basal intracellular calcium concentration ([Ca(2+) ](i)), store operated calcium entry (SOCE) and Orai-1 expression in rat PASMC. Methods: We employed the primary culture method for the rat distal PASMC including the enzymatically dissociation of PASMC from the freshly isolated distal pulmonary artery and the culture of PASMC...
February 12, 2017: Chinese Journal of Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/28205262/modern-multiple-myeloma-therapy-deep-sustained-treatment-response-and-good-clinical-outcomes
#4
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/28201976/immunomodulatory-drugs-imids-in-multiple-myeloma
#5
Shahzad Raza, Rachael A Safyan, Lentzsch Suzanne
Multiple myeloma (MM) is a plasma cell neoplasm that is incurable with conventional therapy. However, the treatment of MM has dramatically changed since the emergence of immunomodulatory drugs and proteasome inhibitors. The improvements in survival are linked to a deeper understanding of the molecular mechanisms of the disease. Thalidomide, although highly active in MM, is associated with considerable toxicity, particularly in older patients. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that represent a promising new class of immunomodulators for treatment of a variety of inflammatory, autoimmune, and neoplastic diseases...
February 13, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28194054/tumor-lysis-syndrome-in-multiple-myeloma-an-increasingly-recognized-risk-a-report-of-seven-cases
#6
Abhijai Singh, Shweta Gupta, Barbara Yim, Romy Thekkekara
Tumor lysis syndrome is a constellation of metabolic disturbances commonly seen during therapy of bulky, rapidly proliferative tumors. Multiple myeloma is a low proliferation tumor with rare incidence of tumor lysis syndrome in the pre-Bortezomib era. Post Bortezomib use, a rise in the incidence of tumor lysis has been noted. We present seven cases of tumor lysis syndrome with three patients in spontaneous tumor lysis and four developing the same after chemotherapy. In the previous studies, elevated LDH and deletion of chromosome 13 has been associated with risk of TLS...
March 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28194052/once-weekly-1-6%C3%A2-mg-m-2-bortezomib-bcd-regimen-in-elderly-patients-with-newly-diagnosed-multiple-myeloma-who-are-unfit-for-standard-dose-chemotherapy
#7
Yong Tang, Ye-Hua Yu, Yi-Yun Yao, Li-Fang Zou, Hong-Ju Dou, Lei Wang, Qi Zhu
Bortezomib has shown anti-myeloma effects in combination with alkylating agents, but clinical benefits can be limited by neurotoxicity. There is less information on the efficacy and tolerability of once-weekly 1.6 mg/m(2) bortezomib combined with cyclophosphamide and dexamethasone (BCD) regimen in elderly patients with newly diagnosed multiple myeloma who are unfit for standard dose chemotherapy. Here, we report our experience of weekly 1.6 mg/m(2) intravenous bortezomib in this group of patients. Between March 2010 and February 2015, we treated 34 newly diagnosed elderly patients with the combination of bortezomib 1...
March 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28193668/towards-selective-mycobacterial-clpp1p2-inhibitors-with-reduced-activity-against-the-human-proteasome
#8
Wilfried Moreira, Sridhar Santhanakrishnan, Grace J Y Ngan, Choon Bing Low, Kanda Sangthongpitag, Anders Poulsen, Brian W Dymock, Thomas Dick
Mycobacterium tuberculosis (TB) is responsible for the greatest number of deaths worldwide due to a bacterial agent. We recently identified bortezomib (1) as a promising anti-TB compound. We showed that 1 inhibits the mycobacterial caseinolytic protease ClpP1P2 and exhibits bactericidal activity and established 1 and ClpP1P2 as an attractive lead/target couple. However, 1 is a human proteasome inhibitor currently approved for cancer therapy, and as such exhibits significant toxicity. Selective inhibition of the bacterial protease over the human proteasome is desirable in order to maintain antibacterial activity while reducing toxicity...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28192613/sniper-tacc3-induces-cytoplasmic-vacuolization-and-sensitizes-cancer-cells-to-bortezomib
#9
Nobumichi Ohoka, Katsunori Nagai, Norihito Shibata, Takayuki Hattori, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
We previously developed a hybrid small molecule SNIPER (Specific and Nongenetic IAP-dependent Protein ERaser) against transforming acidic coiled-coil-3 (TACC3), SNIPER(TACC3), that induces proteasomal degradation of TACC3 protein. In this study, we found that SNIPER(TACC3) induces cytoplasmic vacuolization derived from endoplasmic reticulum (ER) and paraptosis-like cell death selectively in cancer cells. Mechanistic analysis suggests that accumulation of ubiquitylated protein aggregates that requires X-linked inhibitor of apoptosis protein (XIAP) induces ER stress, which results in ER-stress responses involving X-box binding protein-1 (XBP-1) and ER-derived vacuolization in cancer cells...
February 13, 2017: Cancer Science
https://www.readbyqxmd.com/read/28186131/recq1-helicase-is-involved-in-replication-stress-survival-and-drug-resistance-in-multiple-myeloma
#10
E Viziteu, B Klein, J Basbous, Y-L Lin, C Hirtz, C Gourzones, L Tiers, A Bruyer, L Vincent, C Grandmougin, A Seckinger, H Goldschmidt, A Constantinou, P Pasero, D Hose, J Moreaux
Multiple myeloma (MM) is a plasma cell cancer with poor survival, characterized by the expansion of multiple myeloma cells (MMCs) in the bone marrow. Using a microarray-based genome-wide screen for genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 among the most downregulated genes. RecQ helicases are DNA unwinding enzymes involved in the maintenance of chromosome stability. Here, we show that RECQ1 is significantly overexpressed in MMCs compared to normal plasma cells and that increased RECQ1 expression is associated with poor prognosis in three independent cohorts of patients...
February 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28185460/-daratumumab-hope-for-myeloma-patients-a-challenge-for-clinical-laboratories
#11
T Jelínek, M Kořístka, Z Čermáková, R Hájek
Monoclonal antibodies represent a standard part in the treatment of oncologic patients, but their efficacy in multiple myeloma used to be unsatisfactory. Daratumumab monotherapy was approved by the American FDA in 2015, after unprecedented results were obtained in a heavily pre-treated group of patients. In 2016 daratumumab was approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of myeloma patients who have received at least one prior therapy.The toxicity of the drug is low, and is dominated by infusion-related reactions in more or less half of patients...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28185202/erratum-to-bortezomib-interferes-with-adhesion-of-b-cell-precursor-acute-lymphoblastic-leukemia-cells-through-sparc-up-regulation-in-human-bone-marrow-mesenchymal-stromal-stem-cells
#12
Masaki Iwasa, Yasuo Miura, Aya Fujishiro, Sumie Fujii, Noriko Sugino, Satoshi Yoshioka, Asumi Yokota, Terutoshi Hishita, Hideyo Hirai, Akira Andoh, Tatsuo Ichinohe, Taira Maekawa
No abstract text is available yet for this article.
February 9, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28182990/design-synthesis-and-biological-evaluation-of-novel-non-peptide-boronic-acid-derivatives-as-proteasome-inhibitors
#13
Ying Ge, Aibo Li, Jianwei Wu, Haiwei Feng, Letian Wang, Hongwu Liu, Yungen Xu, Qingxiang Xu, Li Zhao, Yuyan Li
A novel series of non-peptide proteasome inhibitors bearing the 1, 4-naphthoquinone scaffold and boronic acid warhead was developed. In the biological evaluation on the chymotrypsin-like activity of human 20S proteasome, five compounds showed IC50 values in the nanomolar range. Docking experiments into the yeast 20S proteasome rationalized their biological activities and allowed further optimization of this interesting class of inhibitors. Within the cellular proliferation inhibition assay and western blot analysis, compound 3e demonstrated excellent anti-proliferative activity against solid tumor cells and clear accumulation of ubiquitinated cellular proteins...
January 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28179738/lenalidomide-bortezomib-and-dexamethasone-rvd-regimen-for-multiple-myeloma
#14
Alexandra P Punke, J Aubrey Waddell, Dominic A Solimando
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast...
January 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/28176474/monoclonal-gammopathy-of-renal-significance-triggering-atypical-haemolytic-uraemic-syndrome
#15
REVIEW
Usman Mahmood, Nicole Isbel, Peter Mollee, Andrew Mallett, Sridevi Govindarajulu, Ross Francis
Haemolytic uraemic syndrome is a rare condition with an overall incidence of one to two cases in a population of 100 000 and approximately 10% of these cases are classified as atypical. Atypical haemolytic uraemic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and acute kidney injury. aHUS can be genetic, acquired or idiopathic (negative genetic screening and no environmental triggers). We describe a case of aHUS triggered by monoclonal gammopathy of renal significance (MGRS) successfully treated with plasmapheresis and a bortezomib-based chemotherapy regimen, resulting in marked improvement in renal function and other markers of haemolysis...
February 2017: Nephrology
https://www.readbyqxmd.com/read/28169430/phase-ii-study-of-bendamustine-bortezomib-and-dexamethasone-bbd-in-the-first-line-treatment-of-patients-with-multiple-myeloma-who-are-not-candidates-for-high-dose-chemotherapy
#16
Jesus G Berdeja, Todd Bauer, Edward Arrowsmith, James Essell, Patrick Murphy, James A Reeves, Ralph V Boccia, William Donnellan, Ian Flinn
The combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for multiple myeloma. The original treatment regimen of bendamustine 80 mg/m(2) , days 1, 4; bortezomib 1·3 mg/m(2) , days 1, 4, 8, 11; dexamethasone 40 mg, days 1, 2, 3, 4 on a 28-day cycle (up to 8 cycles) was efficacious but determined relatively toxic in an interim analysis. The regimen was amended to bendamustine 80 mg/m(2) , days 1, 2; bortezomib 1·3 mg/m(2) , days 1, 8, 15; dexamethasone 20 mg, days 1, 2, 8, 9, 15, 16 every 28 days (up to 8 cycles), then maintenance 1·3 mg/m(2) IV bortezomib every 2 weeks...
February 7, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28162031/successful-treatment-of-refractory-systemic-lupus-erythematosus-using-proteasome-inhibitor-bortezomib-followed-by-belimumab-description-of-two-cases
#17
C Sjöwall, M Hjorth, P Eriksson
Although the putative therapeutic options for patients with systemic lupus erythematosus (SLE) are steadily increasing, refractory disease is indeed a major challenge to many clinicians and patients. The proteasome inhibitor bortezomib - approved for the treatment of multiple myeloma since the beginning of this century - was recently reported successful in twelve cases of refractory SLE by German colleagues. Herein, we describe two Swedish SLE cases with refractory renal and pulmonary manifestations that were rescued by bortezomib as induction of remission followed by monthly doses of belimumab...
January 1, 2017: Lupus
https://www.readbyqxmd.com/read/28161489/antiproliferative-effects-of-bortezomib-in-endothelial-cells-transformed-by-viral-g-protein-coupled-receptor-associated-to-kaposi-s-sarcoma
#18
A Suares, M Mori Sequeiros Garcia, C Paz, V González-Pardo
The Kaposi's Sarcoma-associated Herpes virus G Protein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma. We have previously demonstrated that the proteasome inhibitor Bortezomib inhibits NF-κB pathway, which is required for tumor maintenance in endothelial cells that express vGPCR (vGPCR cells). In this work, we further investigated Bortezomib anti-proliferative mechanism of action. We demonstrated that Bortezomib decreases vGPCR cell number in a dose-dependent manner and induces cell morphology changes...
February 1, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28152955/real-world-treatment-patterns-health-care-resource-utilization-hru-and-costs-among-patients-with-waldenstrom-macroglobulinemia-wm-initiating-therapy
#19
Lorie Ellis, Stephanie Korrer, Stacey DaCosta Byfield
: 17 Background: WM is a rare, indolent B-cell lymphoma with 1000 to 1500 new cases diagnosed annually in the US. The disease is incurable with current therapy. Prior to January 2015 when ibrutinib was approved by the US FDA for WM, there were no therapies approved in this indication. This study describes initial systemic anti-cancer therapy (SACT) and HRU among WM patients (pts). METHODS: A retrospective study using a large, national US claims database from 1/2007-10/2013 was conducted...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28152765/evaluation-of-relative-thrombocytopenia-identification-of-neuropathy-and-bleeding-risk-secondary-to-utilization-of-neuromodulating-agents-in-multiple-myeloma-patients-receiving-autologous-stem-cell-transplant-treated-with-melphalan-bortezomib-and-lenalidomide
#20
Joel Marcus, Robyn Jackson, Marco A Ruiz, Ryan Patrick Griffin, Rubina Hafeez Khan
: 212 Background: Chemotherapy-induced polyneuropathy (CIPN) is a crippling manifestation in multiple myeloma (MM) patients that requires attentiveness to safety and quality of life.(2) Bortezomib, lenalidomide, and melphalan are commonly utilized chemotherapy agents that can cause both CIPN(3,4) and significant myelosuppression. Within this subset of patients we wish to insure efficacy and minimization of neuropathic pain while being mindful of bleeding risks. METHODS: IRB approval was obtained for a retrospective study of patients with MM who received a bone marrow transplant (BMT)...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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