Prognostic significance of esterase gene expression in multiple myeloma

Background Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM). Methods For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM. Results MM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P <0.05). The MMRF CoMMpass dataset provided validation that higher expression of PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis. Conclusions Esterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.Peer reviewe

The Peptide–Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death

Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by clonal plasma cell secretion of misfolded light chains that assemble as toxic amyloid fibrils, depositing in vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell–directed therapeutics are expected to reduce production of toxic light chain by eliminating amyloidogenic cells in bone marrow, thereby diminishing amyloid fibril deposition and providing the potential for organ recovery. Melphalan flufenamide (melflufen) is a first-in-class peptide–drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen is highly lipophilic, permitting rapid uptake by cells, where it is enzymatically hydrolyzed by aminopeptidases, resulting in intracellular accumulation of the alkylating agents, including melphalan. Previous data demonstrating sensitivity of myeloma cells to melflufen suggest that the drug might be useful in AL amyloidosis. We describe the effects of melflufen on amyloidogenic plasma cells in vitro and ex vivo, demonstrating enhanced cytotoxic effects in comparison to melphalan, as well as novel mechanisms of action through the unfolded protein response (UPR) pathway. These findings provide evidence that melflufen-mediated cytotoxicity extends to amyloidogenic plasma cells, and support the rationale for the evaluation of melflufen in patients with AL amyloidosis.Peer reviewe

Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: A systematic analysis across 1997-2013

Background: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. Methods: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. Results: Total research investment for all three diseases was £1.4 billion, and was greatest for HIV (£651.4 million), followed by malaria (£518.7 million) and tuberculosis (£239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (£50,691) appeared the most productive for investment, compared to HIV (£61,971) and malaria (£94,483). By type of science, public health research was most productive for HIV (£27,296) and tuberculosis (£22,273), while phase I-III trials were most productive for malaria (£60,491). According to UK pound per citation, tuberculosis (£1,797) was the most productive area for investment, compared to HIV (£2,265) and malaria (£2,834). Public health research was the most productive type of science for HIV (£2,265) and tuberculosis (£1,797), whereas phase I-III trials were most productive for malaria (£1,713). Conclusions: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations.Infectious Disease Research Networ

Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM

Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

A recently quenched galaxy 700 million years after the Big Bang

© 2024 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Local and low-redshift ($z$10^{10}~M_{\odot}$) and relatively old. Here we report a (mini-)quenched galaxy at z$=$7.3, when the Universe was only 700~Myr old. The JWST/NIRSpec spectrum is very blue ($U$-$V$$=$0.16$\pm0.03$~mag), but exhibits a Balmer break and no nebular emission lines. The galaxy experienced a short starburst followed by rapid quenching; its stellar mass (4-6$\times 10^8~M_\odot$) falls in a range that is sensitive to various feedback mechanisms, which can result in perhaps only temporary quenching.Peer reviewe

JADES: Probing interstellar medium conditions at z∼5.5−9.5z\sim5.5-9.5 with ultra-deep JWST/NIRSpec spectroscopy

We present emission line ratios from a sample of 26 Lyman break galaxies from $z\sim5.5-9.5$ with $-17.0<M_{1500}<-20.4$, measured from ultra-deep JWST/NIRSpec MSA spectroscopy from JADES. We use 28 hour deep PRISM/CLEAR and 7 hour deep G395M/F290LP observations to measure, or place strong constraints on, ratios of widely studied rest-frame optical emission lines including H$\alpha$, H$\beta$, [OII] $\lambda\lambda$3726,3729, [NeIII] $\lambda$3869, [OIII] $\lambda$4959, [OIII] $\lambda$5007, [OI] $\lambda$6300, [NII] $\lambda$6583, and [SII] $\lambda\lambda$6716,6731 in individual $z>5.5$ spectra. We find that the emission line ratios exhibited by these $z\sim5.5-9.5$ galaxies occupy clearly distinct regions of line-ratio space compared to typical z~0-3 galaxies, instead being more consistent with extreme populations of lower-redshift galaxies. This is best illustrated by the [OIII]/[OII] ratio, tracing interstellar medium (ISM) ionisation, in which we observe more than half of our sample to have [OIII]/[OII]>10. Our high signal-to-noise spectra reveal more than an order of magnitude of scatter in line ratios such as [OII]/H$\beta$ and [OIII]/[OII], indicating significant diversity in the ISM conditions within the sample. We find no convincing detections of [NII] in our sample, either in individual galaxies, or a stack of all G395M/F290LP spectra. The emission line ratios observed in our sample are generally consistent with galaxies with extremely high ionisation parameters (log $U\sim-1.5$), and a range of metallicities spanning from $\sim0.1\times Z_\odot$ to higher than $\sim0.3\times Z_\odot$, suggesting we are probing low-metallicity systems undergoing periods of rapid star-formation, driving strong radiation fields. These results highlight the value of deep observations in constraining the properties of individual galaxies, and hence probing diversity within galaxy population.Comment: 20 pages, 9 figures, submitted to Astronomy & Astrophysics, updated values in table

Spectroscopy of four metal-poor galaxies beyond redshift ten

Finding and characterising the first galaxies that illuminated the early Universe at cosmic dawn is pivotal to understand the physical conditions and the processes that led to the formation of the first stars. In the first few months of operations, imaging from the James Webb Space Telescope (JWST) have been used to identify tens of candidates of galaxies at redshift (z) greater than 10, less than 450 million years after the Big Bang. However, none of these candidates has yet been confirmed spectroscopically, leaving open the possibility that they are actually low-redshift interlopers. Here we present spectroscopic confirmation and analysis of four galaxies unambiguously detected at redshift 10.3<z<13.2, previously selected from NIRCam imaging. The spectra reveal that these primeval galaxies are extremely metal poor, have masses between 10^7 and a few times 10^8 solar masses, and young ages. The damping wings that shape the continuum close to the Lyman edge are consistent with a fully neutral intergalactic medium at this epoch. These findings demonstrate the rapid emergence of the first generations of galaxies at cosmic dawn.Comment: 32 pages, 9 figures, Submitte