Bortezomib

PURPOSE OF REVIEW: To review what is currently known about the pathogenesis, diagnosis, treatment, and prevention of acute rejection (AR) in lung transplantation. RECENT FINDINGS: Epigenomic and transcriptomic methods are gaining traction as tools for earlier detection of AR, which still remains primarily a histopathologic diagnosis. SUMMARY: Acute rejection is a common cause of early posttransplant lung graft dysfunction and increases the risk of chronic rejection...

Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti-AML activity of bortezomib (BTZ), emphasizing its anti-LSC potential, using KG-1a cells, an AML cell line with stem-like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem-like features of KG-1a cells, as observed by the reduction in CD34- and CD123-positive cells...

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37...

Iron contributes to tumor initiation and progression; however, excessive intracellular free Fe2+ can be toxic to cancer cells. Our findings confirmed that multiple myeloma (MM) cells exhibited elevated intracellular iron levels and increased ferritin, a key protein for iron storage, compared with normal cells. Interestingly, Bortezomib (BTZ) was found to trigger ferritin degradation, increase free intracellular Fe2+ , and promote ferroptosis in MM cells. Subsequent mechanistic investigation revealed that BTZ effectively increased NCOA4 levels by preventing proteasomal degradation in MM cells...

Despite the emergence of monoclonal antibodies, the prognosis of patients with multiple myeloma (MM) with extramedullary disease remains poor. The present report describes a rare case of daratumumab-refractory MM that was successfully treated with elotuzumab, pomalidomide and dexamethasone. A 66-year-old male patient diagnosed with MM was treated with bortezomib, lenalidomide and dexamethasone, followed by high-dose chemotherapy and autologous stem cell transplantation. Thereafter, the patient was treated with lenalidomide and dexamethasone as maintenance therapy...

For the majority of cytotoxic drug preparations, such as bortezomib, the unit dose information is not available. In addition, there is a lack of information on the physicochemical stability of the pharmaceutical preparation after opening; this information is crucial for its administration to patients in successive visits, and the per-patient cost can be affected. The purpose of our proposed physicochemical stability study is to determine the shelf life of the reconstituted liquid product under refrigeration and clinical practice conditions...

Deletions of chromosome 1p (del(1p)) are a recurrent genomic aberration associated with poor outcome in Multiple myeloma (MM.) TRIM33, an E3 ligase and transcriptional co-repressor, is located within a commonly deleted region at 1p13.2. TRIM33 is reported to play a role in the regulation of mitosis and PARP-dependent DNA damage response (DDR), both of which are important for maintenance of genome stability. Here, we demonstrate that MM patients with loss of TRIM33 exhibit increased chromosomal instability and poor outcome...

OBJECTIVES: Some drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or SIV, but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses. DESIGN: To investigate this hypothesis, drugs were tested ex vivo on Peripheral Blood Mononuclear Cells (PBMC) from nine ART-suppressed individuals...

BACKGROUND: Hypertension is characterized by CD8+ T cell activation and infiltration into peripheral tissues. CD8+ T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome. We hypothesized that immunoproteasomal processing of isoLG-adducts is essential for CD8+ T cell activation and inflammation in hypertension. METHODS: IsoLG adduct processing was studied in murine dendritic cells (DCs), endothelial cells (ECs), and B8 fibroblasts...

Bortezomib (BTZ), a proteasome inhibitor, is a promising therapeutic option for multiple myeloma (MM) patients. However, drug resistance often occurs, leading to disease relapse and poor prognosis. In this study, we aimed to identify novel genes associated with drug resistance and investigate their roles in BTZ resistance. Through the screening of 26 genes frequently associated with chemosensitivity or drug resistance, we discovered that KDM4C, a histone demethylase, exhibited increased expression in BTZ-resistant MM cells compared to their sensitive counterparts...

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy...

No abstract text is available yet for this article.

Bortezomib is the first-line standard and most effective chemotherapeutic for multiple myeloma; however, bortezomib-induced peripheral neuropathy (BIPN) severely affects the chemotherapy regimen and has long-term impact on patients under maintenance therapy. The pathogenesis of BIPN is poorly understood, and basic research and development of BIPN management drugs are in early stages. Besides chemotherapy dose reduction and regimen modification, no recommended prevention and treatment approaches are available for BIPN apart from the International Myeloma Working Group guidelines for peripheral neuropathy in myeloma...

BACKGROUND: Multiple myeloma (MM) represents the second most common hematologic malignancy (15%). Induction with bortezomib, cyclophosphamide, and dexamthasone VCd (d: low dose dexamthasone) regimen is widely used due to its high effectiveness, low toxicity and good tolerability, particularly with renal impairment. Real-world data on the use of VCD in clinical practice is lacking. OBJECTIVES: Evaluate the real-world experience of the VCD regimen. DESIGN: Retrospective...

Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models...

Niemann-Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and β-amyloid peptide...

Spontaneous/atraumatic splenic rupture is rare, and often associated with underlying infectious disease, or haematological malignancy. Plasma cell leukaemia (PCL) is a rare and aggressive subtype of multiple myeloma, with a higher prevalence of hepatosplenomegaly with a bleeding diathesis from secondary to thrombocytopaenia. We report the case of an 82-year-old male presenting to the emergency department with altered mentation and complaints of left abdominal pain. He presented with haemorrhagic shock. Imaging revealed a spontaneous splenic rupture...

Cytogenetic karyotypes such as t(4; 14), del(17p), t(14; 16), t(14; 20), and TP53 mutations are associated with high-risk multiple-myeloma (MM) and indicate poor prognosis. Therefore, cytogenetic testing is extremely important for determining prognosis of MM. However, the aberrant karyotypes reported in the current literature are incomplete. The cytogenetic karyotype 17p gain has not received widespread attention, and its relationship with MM prognosis is unknown; additionally, the prognosis of 17p gain associated with t(4; 14) has not been studied in depth...

No abstract text is available yet for this article.

Histone H1 is involved in chromatin compaction and dynamics. In human cells, the H1 complement is formed by different amounts of somatic H1 subtypes, H1.0-H1.5 and H1X. The amount of each variant depends on the cell type, the cell cycle phase, and the time of development and can be altered in disease. However, the mechanisms regulating H1 protein levels have not been described. We have analyzed the contribution of the proteasome to the degradation of H1 subtypes in human cells using two different inhibitors: MG132 and bortezomib...