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https://www.readbyqxmd.com/read/28345001/effective-depletion-of-pre-existing-anti-aav-antibodies-requires-broad-immune-targeting
#1
Victoria M Velazquez, Aaron S Meadows, Ricardo J Pineda, Marybeth Camboni, Douglas M McCarty, Haiyan Fu
Pre-existing antibodies (Abs) to AAV pose a critical challenge for the translation of gene therapies. No effective approach is available to overcome pre-existing Abs. Given the complexity of Ab production, overcoming pre-existing Abs will require broad immune targeting. We generated a mouse model of pre-existing AAV9 Abs to test multiple immunosuppressants, including bortezomib, rapamycin, and prednisolone, individually or in combination. We identified an effective approach combining rapamycin and prednisolone, reducing serum AAV9 Abs by 70%-80% at 4 weeks and 85%-93% at 8 weeks of treatment...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28341300/a-phase-i-pharmacokinetic-study-of-intraperitoneal-bortezomib-and-carboplatin-in-patients-with-persistent-or-recurrent-ovarian-cancer-an-nrg-oncology-gynecologic-oncology-group-study
#2
Danielle A Jandial, William E Brady, Stephen B Howell, Heather A Lankes, Russell J Schilder, Jan H Beumer, Susan M Christner, Sandra Strychor, Matthew A Powell, Andrea R Hagemann, Kathleen N Moore, Joan L Walker, Paul A DiSilvestro, Linda R Duska, Paula M Fracasso, Don S Dizon
PURPOSE: Intraperitoneal (IP) therapy improves survival compared to intravenous (IV) treatment for women with newly diagnosed, optimally cytoreduced, ovarian cancer. However, the role of IP therapy in recurrent disease is unknown. Preclinical data demonstrated IP administration of the proteasome inhibitor, bortezomib prior to IP carboplatin increased tumor platinum accumulation resulting in synergistic cytotoxicity. We conducted this phase I trial of IP bortezomib and carboplatin in women with recurrent disease...
March 21, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28339079/a-p110%C3%AE-specific-inhibitor-combined-with-bortezomib-blocks-drug-resistance-properties-of-ebv-related-b-cell-origin-cancer-cells-via-regulation-of-nf-%C3%AE%C2%BAb
#3
Ga Bin Park, Yoon Hee Chung, Jee-Yeong Jeong, Daejin Kim
Epstein-Barr virus (EBV) infection is closely related to carcinogenesis of various cancers, and is also associated with the development of drug resistance in cancer stem cells. However, in EBV-positive cancer cells, the mechanistic details of the downstream signaling and the connection of PI3K with the NF-κB pathway for development of drug resistance remain controversial. Diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) cells infected by EBV display drug resistance-related proteins (MDR1, MRP1 and MRP2) and stem cell markers (OCT4 and SOX2)...
March 21, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28338672/posttransplant-maintenance-therapy-in-multiple-myeloma-the-changing-landscape
#4
REVIEW
S Sengsayadeth, F Malard, B N Savani, L Garderet, M Mohty
Transplant-eligible patients with multiple myeloma (MM) now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant (ASCT), consolidation therapy and posttransplant maintenance therapy. Standard of care for newly diagnosed, fit patients includes ASCT and, often nowadays, posttransplant maintenance. Several large studies have shown the efficacy of maintenance with thalidomide, lenalidomide and bortezomib in the treatment scheme of MM with regards to prolonging progression-free survival and, to a lesser degree, overall survival...
March 24, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28336807/pmp22-regulates-self-renewal-and-chemoresistance-of-gastric-cancer-cells
#5
Wangyu Cai, Gang Chen, Qicong Luo, Jun Liu, Xiaofeng Guo, Tian Zhang, Fei Ma, Liang Yuan, Boan Li, Jianchun Cai
Cancer stem cells (CSCs) possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the Explorer Antibody Microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation...
March 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28334762/missense-uros-mutations-causing-congenital-erythropoietic-porphyria-reduce-uros-homeostasis-that-can-be-rescued-by-proteasome-inhibition
#6
Jean-Marc Blouin, Ganeko Bernardo-Seisdedos, Emma Sasso, Julie Esteve, Cécile Ged, Magalie Lalanne, Arantza Sanz-Parra, Pedro Urquiza, Hubert de Verneuil, Oscar Millet, Emmanuel Richard
Congenital erythropoietic porphyria (CEP) is an inborn error of heme biosynthesis characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in deleterious porphyrin accumulation in blood cells responsible for hemolytic anemia and cutaneous photosensitivity. We analyzed here the molecular basis of UROS impairment associated with twenty nine UROS missense mutations actually described in CEP patients. Using a computational and biophysical joint approach we predicted that most disease-causing mutations would affect UROS folding and stability...
February 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334751/atp13a2-park9-regulates-endo-lysosomal-cargo-sorting-and-proteostasis-through-a-novel-pi-3-5-p2-mediated-scaffolding-function
#7
S Demirsoy, S Martin, S Motamedi, S van Veen, T Holemans, C Van den Haute, A Jordanova, V Baekelandt, P Vangheluwe, P Agostinis
ATP13A2 (also called PARK9), is a transmembrane endo-/lysosomal-associated P5 type transport ATPase. Loss-of-function mutations in ATP13A2 result in the Kufor-Rakeb Syndrome (KRS), a form of autosomal Parkinson's disease (PD). In spite of a growing interest in ATP13A2, very little is known about its physiological role in stressed cells. Recent studies suggest that the N-terminal domain of ATP13A2 may hold key regulatory functions, but their nature remains incompletely understood. To this end, we generated a set of melanoma and neuroblastoma cell lines stably overexpressing wild-type (WT), catalytically inactive (D508N) and N-terminal mutants, or shRNA against ATP13A2...
February 22, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334621/sequential-cyclophosphamide-bortezomib-dexamethasone-unmasks-the-harmful-cardiac-effect-of-dexamethasone-in-primary-light-chain-cardiac-amyloidosis
#8
Fabien Le Bras, Valerie Molinier-Frenkel, Aziz Guellich, Jehan Dupuis, Karim Belhadj, Soulef Guendouz, Karima Ayad, Magali Colombat, Nicole Benhaiem, Claire Marie Tissot, Anne Hulin, Arnaud Jaccard, Thibaud Damy
Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains...
March 20, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28333868/proteasome-inhibitor-induced-gastrointestinal-toxicity
#9
Romany L Stansborough, Rachel J Gibson
PURPOSE OF REVIEW: Gastrointestinal toxicities are commonly reported following treatment with proteasome inhibitors. The first-generation proteasome inhibitor, bortezomib, induces significant gastrointestinal side effects including nausea, vomiting, diarrhoea, and constipation, occurring in up to 84% of patients. Despite the development of safer proteasome inhibitors, such as carfilzomib, gastrointestinal toxicities remain some of the most common side effects. This review aims to summarize the previous literature on proteasome inhibitor-induced gastrointestinal toxicities, report on recent updates in the field, and investigate possible mechanisms of this toxicity...
March 22, 2017: Current Opinion in Supportive and Palliative Care
https://www.readbyqxmd.com/read/28331448/antibody-mediated-rejection-a-review
#10
Jorge Carlos Garces, Sixto Giusti, Catherine Staffeld-Coit, Humberto Bohorquez, Ari J Cohen, George E Loss
BACKGROUND: Chronic antibody injury is a serious threat to allograft outcomes and is therefore the center of active research. In the continuum of allograft rejection, the development of antibodies plays a critical role. In recent years, an increased recognition of molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However, several pathways are still unknown, which accounts for the lack of efficacy of some of the currently available agents that are used to treat rejection...
2017: Ochsner Journal
https://www.readbyqxmd.com/read/28327055/the-evaluation-of-the-anti-cancer-activity-of-ixazomib-on-caco2-colon-solid-tumor-cells-comparison-with-bortezomib
#11
Selin Engür, Miriş Dikmen
Proteasome inhibition has recently emerged as a clinically effective anticancer therapeutic approach. The first proteasome inhibitor, bortezomib (Velcade, PS-341), and new proteasome inhibitors including ixazomib have become more important in the development of targeted cancer therapies. Under physiological conditions, MLN9708 (ixazomib citrate), the stable citrate ester drug substance, hydrolyzes rapidly to MLN2238 (ixazomib), the biologically active boronic acid. It is a second-generation proteasome inhibitor, similar to the well-known proteasome inhibitor bortezomib, which is currently being investigated in phase 3 trials as a treatment for multiple Myeloma...
March 22, 2017: Acta Clinica Belgica
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
#12
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/28323983/autophagic-degradation-of-collagen-1a1-by-cortisol-in-human-amnion-fibroblasts
#13
Yabing Mi, Wangsheng Wang, Chuyue Zhang, Chao Liu, Jiangwen Lu, Wenjiao Li, Rujuan Zuo, Leslie Myatt, Kang Sun
Rupture of fetal membranes can initiate parturition at both term and preterm. Collagen is the crucial factor determining the tensile strength of the membranes. Toward the end of gestation, a feed-forward regeneration of cortisol via 11β-hydroxysteroid dehydrogenase 1 exists in fetal membranes. It remains undetermined whether cortisol contributes to collagen reduction in fetal membranes. Here we have examined whether cortisol accumulation is a causative factor for collagen reduction in human amnion fibroblasts, the major source of collagens in the membranes...
January 17, 2017: Endocrinology
https://www.readbyqxmd.com/read/28322253/ubiquitylation-of-p62-sequestosome1-activates-its-autophagy-receptor-function-and-controls-selective-autophagy-upon-ubiquitin-stress
#14
Hong Peng, Jiao Yang, Guangyi Li, Qing You, Wen Han, Tianrang Li, Daming Gao, Xiaoduo Xie, Byung-Hoon Lee, Juan Du, Jian Hou, Tao Zhang, Hai Rao, Ying Huang, Qinrun Li, Rong Zeng, Lijian Hui, Hongyan Wang, Qin Xia, Xuemin Zhang, Yongning He, Masaaki Komatsu, Ivan Dikic, Daniel Finley, Ronggui Hu
Alterations in cellular ubiquitin (Ub) homeostasis, known as Ub stress, feature and affect cellular responses in multiple conditions, yet the underlying mechanisms are incompletely understood. Here we report that autophagy receptor p62/sequestosome-1 interacts with E2 Ub conjugating enzymes, UBE2D2 and UBE2D3. Endogenous p62 undergoes E2-dependent ubiquitylation during upregulation of Ub homeostasis, a condition termed as Ub(+) stress, that is intrinsic to Ub overexpression, heat shock or prolonged proteasomal inhibition by bortezomib, a chemotherapeutic drug...
March 21, 2017: Cell Research
https://www.readbyqxmd.com/read/28320703/case-of-lymphadenopathy-with-lytic-bone-lesions
#15
Siddhesh Arun Kalantri, Uttam Kumar Nath, Debasis Banerjee, Maitreyee Bhattacharyya
Plasmablastic lymphoma, a rare highly aggressive non-Hodgkin's lymphoma subtype, often associated with HIV infection, is a close differential diagnosis of plasmablastic myeloma. The 2 conditions may be morphologically and immunophenotypically identical. However, differentiating between the 2 conditions is critical for adequate patient management. Herein, we describe an unusual case of plasmablastic myeloma with biclonal gammopathy which was initially diagnosed as plasmablastic lymphoma based on lymph node biopsy and immunohistochemistry (IHC) results...
March 20, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28317148/bortezomib-induced-peripheral-neuropathy-a-genome-wide-association-study-on-multiple-myeloma-patients
#16
Chiara Campo, Miguel Inacio da Silva Filho, Niels Weinhold, Seyed Hamidreza Mahmoudpour, Hartmut Goldschmidt, Kari Hemminki, Maximilian Merz, Asta Försti
The proteasome-inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome-wide association study on 646 bortezomib-treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment...
March 20, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28317028/mycobacterial-caseinolytic-protease-gene-regulator-clgr-is-a-substrate-of-caseinolytic-protease
#17
Yoshiyuki Yamada, Thomas Dick
The mycobacterial caseinolytic protease ClpP1P2 is a degradative protease that recently gained interest as a genetically and pharmacologically validated drug target for tuberculosis. The first whole-cell active ClpP1P2 inhibitor, the human proteasome inhibitor bortezomib, is currently undergoing lead optimization to introduce selectivity for the bacterial target. How inhibition of ClpP1P2 translates into whole-cell antimicrobial activity is little understood. Previous work has shown that the caseinolytic protease gene regulator ClgR is an activator of the clpP1P2 genes and also suggested that this transcription factor may be a substrate of the protease...
March 2017: MSphere
https://www.readbyqxmd.com/read/28306593/current-concepts-for-sensitized-patients-before-transplantation
#18
Dael Geft, Jon Kobashigawa
PURPOSE OF REVIEW: Antibody allosensitization poses a major immunologic challenge for patients awaiting heart transplantation. It is associated with significant morbidity and mortality for both pretransplant and posttransplant patients by prolonging wait times to transplant and increasing posttransplant rejection and vasculopathy. Many questions remain regarding methods and interpretation of antibody detection, the relevance of sensitization in specific patient populations such as those with mechanical circulatory support and the ideal strategies for desensitization...
March 16, 2017: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/28306371/carfilzomib-and-dexamethasone-vs-bortezomib-and-dexamethasone-in-patients-with-relapsed-multiple-myeloma-results-of-the-phase-3-study-endeavor-nct01568866-according-to-age-subgroup
#19
Heinz Ludwig, Meletios A Dimopoulos, Philippe Moreau, Wee-Joo Chng, Hartmut Goldschmidt, Roman Hájek, Thierry Facon, Ludek Pour, Ruben Niesvizky, Albert Oriol, Laura Rosiñol, Aleksandr Suvorov, Gianluca Gaidano, Tomas Pika, Katja Weisel, Vesselina Goranova-Marinova, Antonio Palumbo, Heidi H Gillenwater, Nehal Mohamed, Sanjay Aggarwal, Shibao Feng, Douglas Joshua
No abstract text is available yet for this article.
March 17, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28304402/prospective-longitudinal-study-on-quality-of-life-in-relapsed-refractory-multiple-myeloma-patients-receiving-second-or-third-line-lenalidomide-or-bortezomib-treatment
#20
X Leleu, C Kyriakou, I Vande Broek, P Murphy, P Bacon, P Lewis, H Gilet, B Arnould, M T Petrucci
Treatment advances for multiple myeloma (MM) that have prolonged survival emphasise the importance of measuring patients' health-related quality of life (HRQoL) in clinical studies. HRQoL/functioning and symptoms of patients with relapsed/refractory MM (RRMM) receiving second- or third-line lenalidomide or bortezomib treatment were measured in a prospective European multicentre, observational study at different time points. At baseline, patients in the lenalidomide cohort were frailer than in the bortezomib cohort with more rapid disease progression at study entry (more patients with Eastern Cooperative Oncology Group performance status >2, shorter time from diagnosis, more chronic heart failure, higher serum creatinine levels, more patients with dialysis required)...
March 17, 2017: Blood Cancer Journal
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