Internal ribosome entry sites enhance translation in trans in antisense non-coding SINEUP and circular RNAs.

Sequences in the 5'-untranslated regions of cellular and viral mRNAs can function as internal ribosome entry sites (IRESs), driving cis-acting translation of the downstream protein-coding open reading frame. Here we demonstrate that RNA sequences with either newly identified or well-characterized IRES activity can also induce trans-acting translation of an independent mRNA species through an antisense sequence. SINEUPs are antisense long non-coding RNAs that enhance the translation of overlapping sense mRNAs in trans by employing two critical domains: the invSINEB2 sequence, which up-regulates translation (effector domain), and an antisense region providing target specificity (binding domain).

Bortezomib-melphalan-prednisone versus lenalidomide-dexamethasone in elderly patients with multiple myeloma: the Real MM phase IV trial.

Not available.

Carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed myeloma ineligible for autologous stem-cell transplantation (EMN20): a randomised, open-label, multicentre, phase 3 trial.

Background: Before the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment for patients with newly diagnosed transplant-ineligible multiple myeloma, lenalidomide-dexamethasone was a standard of care. We aimed to explore whether addition of the second-generation proteasome inhibitor carfilzomib to lenalidomide-dexamethasone improved the rates of measurable residual disease (MRD) negativity and progression-free survival.

Methods: EMN20 is a randomised, open-label, multicentre, phase 3 trial comparing weekly carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma, conducted in 27 centres in Italy.

A structural element within the 5'UTR of β-catenin mRNA modulates its translation under hypoxia.

Tight regulation of translation initiation is crucial for cellular adaptation to environmental changes. Stress conditions like hypoxia trigger translational reprogramming of mRNAs encoding proteins essential for stress recovery and cell survival. Recent studies highlight alternative translation initiation pathways based on specific motifs in mRNA 5' untranslated regions (5'UTRs).

Clinicians' Perspectives and Methodological Application of Fluorescence in situ Hybridization (FISH) to Define Cytogenetic Risk in Multiple Myeloma: An Italian, Real-World, Survey-Based Report From the European Myeloma Network (EMN) Italy.

Background: Fluorescence in situ hybridization (FISH) is the standard technique for the prognostic detection of cytogenetic abnormalities (CA) in multiple myeloma (MM). In Italy, the application of practical guidelines for FISH testing in clinical studies and the degree of standardization of laboratory techniques are largely unknown.

Methods: We conducted a survey from April to July 2023 among 70 MM-treating centers associated with the European Myeloma Network Italy and geographically well distributed across Italy.

The bone marrow NK-cell profile predicts MRD negativity in patients with multiple myeloma treated with daratumumab-based therapy.

Natural killer (NK) cells are important effector cells in antibody-based immune therapies for multiple myeloma (MM) through antibody-dependent cellular cytotoxicity. Here, we used single-cell transcriptomics, flow cytometry, and functional assays to investigate the bone marrow NK-cell compartment of patients with MM at diagnosis and during treatment. We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK-cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab.

Overview of 1q abnormalities in multiple myeloma: scientific opinions from Italian experts.

Multiple myeloma (MM) is a haematological malignancy characterised by high genomic heterogeneity. One of the most common cytogenic abnormalities in MM is the gain of genetic material at the long arm (q) of chromosome 1 (+ 1q). While many mechanisms of resistance have been associated with + 1q alterations (e.

Minimal Residual Disease-Based End Point for Accelerated Assessment of Clinical Trials in Multiple Myeloma: A Pooled Analysis of Individual Patient Data From Multiple Randomized Trials.

Purpose: Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.

Allocation and validation of the second revision of the International Staging System in the ICARIA-MM and IKEMA studies.

The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs.

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events.

Genomic and immune determinants of resistance to daratumumab-based therapy in relapsed refractory multiple myeloma.

Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody (MoAb) daratumumab, have shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), leading to a considerable increase in progression-free survival. However, a large fraction of patients inevitably relapse. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676).

Additional copies of 1q negatively impact the outcome of multiple myeloma patients and induce transcriptomic deregulation in malignant plasma cells.

Additional copies of chromosome 1 long arm (1q) are frequently found in multiple myeloma (MM) and predict high-risk disease. Available data suggest a different outcome and biology of patients with amplification (Amp1q, ≥4 copies of 1q) vs. gain (Gain1q, 3 copies of 1q) of 1q.

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature.

Crystal structure of archaeal IF5A-DHS complex reveals insights into the hypusination mechanism.

The translation factor IF5A is highly conserved in Eukarya and Archaea and undergoes a unique post-translational hypusine modification by the deoxyhypusine synthase (DHS) enzyme. DHS transfers the butylamine moiety from spermidine to IF5A using NAD as a cofactor, forming a deoxyhypusine intermediate. IF5A is a key player in protein synthesis, preventing ribosome stalling in proline-rich sequences during translation elongation and facilitating translation elongation and termination.

Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma.

Anti-CD38 antibody therapies have transformed multiple myeloma (MM) treatment. However, a large fraction of patients inevitably relapses. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676 ).

Predictors of unsustained measurable residual disease negativity in patients with multiple myeloma.

The prognostic impact of achieving and in particular maintaining measurable residual disease (MRD) negativity in multiple myeloma is now established; therefore, identifying among MRD-negative patients the ones at higher risk of losing MRD negativity is of importance. We analyzed predictors of unsustained MRD negativity in patients enrolled in the FORTE trial (NCT02203643). MRD was performed by multiparameter flow cytometry (sensitivity of 10-5) at premaintenance and every 6 months thereafter.