A multicenter study of the efficacy and safety of treatments (endovascular or conservative) in small intracranial aneurysms in Colombia.

BACKGROUND: The registry of cerebral aneurysms <5 mm, known for their low risk of rupture, is significant, given their high incidence globally. Our study aimed to identify, in small aneurysms (<5 mm), the potential morphological characteristics, risk factors that can predict the risk of rupture, and the risk or benefit of treating them with endovascular or conservative treatment in ruptured and unruptured intracranial aneurysms. METHODS: The medical records of patients with cerebral aneurysms <5 mm were retrospectively reviewed between January 2014 and December 2022 at two neurovascular centers in Colombia. We evaluated clinical and angiographic outcomes using statistical tests. RESULTS: Two hundred fifty-six patients (425 intracranial aneurysms) were registered in the database. Two hundred and seventy-five IA were treated with endovascular treatment: 70 ruptured aneurysms and 205 unruptured aneurysms. One hundred fifty intracranial aneurysms underwent conservative treatment (follow-up). Women accounted for 82.1% of cases. Most cases were incidentally diagnosed (83.5%). After a year of follow-up, 87.3% of unruptured and 67.1% of ruptured intracranial aneurysms had an mRS 0-2. In the Raymond-Roy occlusion classification, among 101 unruptured intracranial aneurysms embolized were 53 cases class I, and among 66 ruptured intracranial aneurysms embolized, 67.1% were class I. CONCLUSION: Endovascular therapy for aneurysms <5 mm appears to be a technically feasible treatment, with satisfactory occlusion rates and few re-treatments at the 12-month follow-up. The complication rates were similar to those reported in studies on small aneurysms.

Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia.

The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.

The proton-sensing receptors TDAG8 and GPR4 are differentially expressed in human and mouse oligodendrocytes: Exploring their role in neuroinflammation and multiple sclerosis.

Acidosis is one of the hallmarks of demyelinating central nervous system (CNS) lesions in multiple sclerosis (MS). The response to acidic pH is primarily mediated by a family of G protein-coupled proton-sensing receptors: OGR1, GPR4 and TDAG8. These receptors are inactive at alkaline pH, reaching maximal activation at acidic pH. Genome-wide association studies have identified a locus within the TDAG8 gene associated with several autoimmune diseases, including MS. Accordingly, we here found that expression of TDAG8, as opposed to GPR4 or OGR1, is upregulated in MS plaques. This led us to investigate the expression of TDAG8 in oligodendrocytes using mouse and human in vitro and in vivo models. We observed significant upregulation of TDAG8 in human MO3.13 oligodendrocytes during maturation and in response to acidic conditions. However, its deficiency did not impact normal myelination in the mouse CNS, and its expression remained unaltered under demyelinating conditions in mouse organotypic cerebellar slices. Notably, our data revealed no expression of TDAG8 in primary mouse oligodendrocyte progenitor cells (OPCs), in contrast to its expression in primary human OPCs. Our investigations have revealed substantial species differences in the expression of proton-sensing receptors in oligodendrocytes, highlighting the limitations of the employed experimental models in fully elucidating the role of TDAG8 in myelination and oligodendrocyte biology. Consequently, the study does not furnish robust evidence for the role of TDAG8 in such processes. Nonetheless, our findings tentatively point towards a potential association between TDAG8 and myelination processes in humans, hinting at a potential link between TDAG8 and the pathophysiology of MS and warrants further research.

Emerging roles of senolytics/senomorphics in HIV-related co-morbidities.

Human immunodeficiency virus (HIV) is known to cause cellular senescence and inflammation among infected individuals. While the traditional antiretroviral therapies (ART) have allowed the once fatal infection to be managed effectively, the quality of life of HIV patients on prolonged ART use is still inferior. Most of these individuals suffer from life-threatening comorbidities like chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and diabetes, to name a few. Interestingly, cellular senescence is known to play a critical role in the pathophysiology of these comorbidities as well. It is therefore important to understand the role of cellular senescence in the disease progression and co-morbidity development in HIV-infected individuals. In this respect, use of senolytic/senomorphic drugs as combination therapy with ART would be beneficial for HIV patients. This review provides a critical analysis of the current literature to determine the potential and efficacy of using senolytics/senotherapeutics in managing HIV infection, latency, and associated co-morbidities in humans. The various classes of senolytics have been studied in detail to focus on their potential to combat against HIV infections and associated pathologies with advancing age.

A kernel-based machine learning potential and quantum vibrational state analysis of the cationic Ar hydride (Ar2H+).

One of the most fascinating discoveries in recent years, in the cold and low pressure regions of the universe, was the detection of ArH+ and HeH+ species. The identification of such noble gas-containing molecules in space is the key to understanding noble gas chemistry. In the present work, we discuss the possibility of [Ar2H]+ existence as a potentially detectable molecule in the interstellar medium, providing new data on possible astronomical pathways and energetics of this compound. As a first step, a data-driven approach is proposed to construct a full 3D machine-learning potential energy surface (ML-PES) via the reproducing kernel Hilbert space (RKHS) method. The training and testing data sets are generated from CCSD(T)/CBS[56] computations, while a validation protocol is introduced to ensure the quality of the potential. In turn, the resulting ML-PES is employed to compute vibrational levels and molecular spectroscopic constants for the cation. In this way, the most common isotopologue in ISM, [36Ar2H]+, was characterized for the first time, while simultaneously, comparisons with previously reported values available for [40Ar2H]+ are discussed. Our present data could serve as a benchmark for future studies on this system, as well as on higher-order cationic Ar-hydrides of astrophysical interest.

Mechanosensitive Ion Channels: Their Physiological Importance and Potential Key Role in Cancer.

Mechanosensitive ion channels comprise a broad group of proteins that sense mechanical extracellular and intracellular changes, translating them into cation influx to adapt and respond to these physical cues. All cells in the organism are mechanosensitive, and these physical cues have proven to have an important role in regulating proliferation, cell fate and differentiation, migration and cellular stress, among other processes. Indeed, the mechanical properties of the extracellular matrix in cancer change drastically due to high cell proliferation and modification of extracellular protein secretion, suggesting an important contribution to tumor cell regulation. In this review, we describe the physiological significance of mechanosensitive ion channels, emphasizing their role in cancer and immunity, and providing compelling proof of the importance of continuing to explore their potential as new therapeutic targets in cancer research.

Ar+ ArH+ Reactive Collisions of Astrophysical Interest: The Case of 36 Ar.

The reactive collision between 36 Ar and the 36 ArH+ species has been investigated by means of quantum mechanical (QM), quasiclassical trajectories (QCT) and statistical quantum mechanical (SQM) approaches. Reaction probabilities, cross sections as a function of the energy and rate constants in terms of the temperature have been obtained. Cumulative distributions as a function of the collision time and the inspection of selected QCT corresponding to specific dynamical mechanisms have been analysed. Predictions by means of the SQM method are in good agreement with the QM results, thus supporting the complex-forming nature of the process.

Quantum computations in heavy noble-gas hydride cations: Reference energies and new spectroscopic data.

Computational quantum chemistry has become a powerful tool with a wide range of possibilities to solve chemical-physical problems. As a result of this, the interest in the applications of computational quantum chemistry has expanded considerably, and has opened up novel research opportunities. In particular, those related to the characterization of heavy-atoms complexes, as most electronic structure calculations for such systems struggle with the problem posed by the large number of electrons present in them, and consequently, the introduction of relativistic effects. The present study performed an exhaustive assess to characterized the uncommon NgH+ (Ng = Kr, Xe, and Rn) hydride cations in order to provide accurate rovibrational data of their isotopes to assist in the laboratory characterization or even their astronomical detection. Scalar relativistic effects were included, and the ground and first electronically exited states potential curves were obtained from benchmark ab initio CCSD(T)/CBS and MRCI+Q electronic structure calculations. Next, such interaction potentials, correctly extended to long-range asymptotic regions, were employed in quantum bound state calculations and molecular spectroscopic constants were determined for the most abundance 84Kr, 132Xe, and 222Rn isotopes. Our results were discussed in comparison with available experimental and previous theoretical estimates, aiming to treat accuracy issues. The new sets provide reference data that could serve for spectroscopic characterization of such low abundance and high radioactive species.

Dedicated macrophages organize and maintain the enteric nervous system.

Correct development and maturation of the enteric nervous system (ENS) is critical for survival1. At birth, the ENS is immature and requires considerable refinement to exert its functions in adulthood2. Here we demonstrate that resident macrophages of the muscularis externa (MMϕ) refine the ENS early in life by pruning synapses and phagocytosing enteric neurons. Depletion of MMϕ before weaning disrupts this process and results in abnormal intestinal transit. After weaning, MMϕ continue to interact closely with the ENS and acquire a neurosupportive phenotype. The latter is instructed by transforming growth factor-ß produced by the ENS; depletion of the ENS and disruption of transforming growth factor-ß signalling result in a decrease in neuron-associated MMϕ associated with loss of enteric neurons and altered intestinal transit. These findings introduce a new reciprocal cell-cell communication responsible for maintenance of the ENS and indicate that the ENS, similarly to the brain, is shaped and maintained by a dedicated population of resident macrophages that adapts its phenotype and transcriptome to the timely needs of the ENS niche.

Low rate of vaccination and risk of incident hepatitis A among HIV-infected men who have sex with men in Seville, Southern Spain.

BACKGROUND: Periodic outbreaks of hepatitis A (HAV) infection in men who have sex with men (MSM) have been reported. Low vaccination uptake in HIV-infected individuals could drive new outbreaks. We aimed at evaluating the incidence of and risk factors for HAV infection in people living with HIV (PLWH) in our area. We also assessed the rates of HAV vaccination. METHODS: This was a prospective cohort study. 915 patients were included, 272 (30%) of them were anti-HAV seronegative at baseline. RESULTS: Twenty-six (9.6%) susceptible individuals became infected. Incident cases peaked in 2009-2010 and 2017-2018. Incident HAV infection was independently associated with MSM [adjusted odds ratio (95% confidence ratio): 4.39 (1.35-14.27), p=0.014]. One hundred and five (38.6%) HAV seronegative patients were vaccinated, 21 (20%) of them did not respond, and one (1%) patient lost immunity against HAV. Four (29%) non-responders to vaccination showed incident HAV 5-9 years afterwards. CONCLUSIONS: The incidence of HAV infection in a cohort of well-controlled PLWH remains low and stable, with intermittent outbreaks involving mainly non-immunized MSM. A significant proportion of PLWH remain susceptible to HAV infection due to insufficient vaccine uptake and limited response to vaccination. Importantly, patients not responding to HAV vaccination continue at risk of infection.

Lower estimated glomerular filtration rate at admission is associated with a worse outcome in older patients with hip fracture who undergo surgical treatment.

BACKGROUND: We assessed the relationship of estimated glomerular filtration rate values at hospital admission on the outcome of surgically treated older adults who had suffered a hip fracture. METHODS: Prospective study that included patients > 65 years of age, surgically treated for primary hip fracture, with no pathologic or high-energy trauma aetiology admitted to a tertiary teaching hospital between 2018 and 2019. We stratified patients based on their estimated glomerular filtration rate at admission and examined its association to demographic and clinical variables, including 90-day post-discharge mortality. RESULTS: The study included 942 hip fracture patients. Lowered estimated glomerular filtration rate was significantly associated to a worsening of the functional status, higher incidence of medical postoperative complications, higher postoperative renal dysfunction, and greater number of blood transfusions. Mortality displayed a staircase pattern, increasing with decreasing estimated glomerular filtration rate. Patients with estimated glomerular filtration rate <60 had significantly higher mortality at 90 days after discharge. In-hospital mortality rate was 10.7% in hip fracture patients with chronic kidney disease who experienced a significant variation in the estimated glomerular filtration rate (>5 mL/min/1.73m2) on admission in comparison to baseline values. CONCLUSION: Older adult patients treated for hip fracture with lower glomerular filtration rate values have poorer functional status and worse prognosis. A significant clinical variation of estimated glomerular filtration rate upon hospital admission for hip fracture may be associated with increased in-hospital mortality of chronic kidney disease patients.

El filtrado glomerular bajo al ingreso se relaciona con un peor pronóstico en pacientes mayores con fractura de cadera tratados quirúrgicamente / Lower estimated glomerular filtration rate at admission is associatedwith a worse outcome in older patients with hip fracture who undergosurgical treatment

Fundamento: Evaluar la influencia de los valores de filtrado glomerular estimado (eFG) al ingreso en el pronóstico de los pacientes mayores con fractura de cadera tratados quirúrgicamente.Métodos: Estudio prospectivo de pacientes >65 años, tratados quirúrgicamente por una fractura de cadera primaria, sin etiología tumoral o traumatismo de alta energía, en un hospital universitario terciario entre 2018 y 2019. Estratificamos a los pacientes según el FG al ingreso y estudiamos su asociación con distintas variables demográficas y clínicas, incluida la mortalidad hasta 90 días después del alta hospitalaria.Resultados: Se incluyeron 942 pacientes. La disminución del eFG se asoció significativamente a peor estado funcional, mayor incidencia de complicaciones médicas postoperatorias, mayor disfunción renal postoperatoria y mayor necesidad de transfusión sanguínea. La mortalidad mostró un patrón en escalera que aumentaba con la disminución del eFG. A los 90 días, la mortalidad fue significativamente mayor en pacientes con eFG <60. Los pacientes con enfermedad renal crónica que sufrían una fractura de cadera y experimentan al ingreso una variación significativa del eFG (>5 mL/min/1,73m2) respecto a los valores basales mostraron una tasa de mortalidad intrahospitalaria del 10,7%.Conclusiones: Los pacientes ancianos tratados quirúrgicamente por fractura de cadera con valores más bajos de tasa de eFG presentan peor estado funcional y peor pronóstico. Una variación clínica significativa del FG (>5) en el momento del ingreso hospitalario tras una fractura de cadera podría asociarse a un aumento de la mortalidad intrahospitalaria de los pacientes con insuficiencia renal crónica.(AU)

Background: We assessed the relationship of estimated glomerular filtration rate values at hospital admission on the outcome of surgically treated older adults who had suffered a hip fracture. Methods: Prospective study that included patients > 65 years of age, surgically treated for primary hip fracture, with no pathologic or high-energy trauma aetiology admitted to a tertiary teaching hospital between 2018 and 2019. We stratified patients based on their estimated glomerular filtration rate at admission and examined its association to demographic and clinical variables, including 90-day post-discharge mortality. Results: The study included 942 hip fracture patients. Lowered estimated glomerular filtration rate was significantly associated to a worsening of the functional status, higher incidence of medical postoperative complications, higher postoperative renal dysfunction, and greater number of blood transfusions. Mortality displayed a staircase pattern, increasing with decreasing estimated glomerular filtration rate. Patients with estimated glomerular filtration rate <60 had significantly higher mortality at 90 days after discharge. In-hospital mortality rate was 10.7% in hip fracture patients with chronic kidney disease who experienced a significant variation in the estimated glomerular filtration rate (>5 mL/min/1.73m2 ) on admission in comparison to baseline values. Conclusion: Older adult patients treated for hip fracture with lower glomerular filtration rate values have poorer functional status and worse prognosis. A significant clinical variation of estimated glomerular filtration rate upon hospital admission for hip fracture may be associated with increased in-hospital mortality of chronic kidney disease patients.(AU)

Developing a glyphosate-bioremediation strategy using plants and actinobacteria: Potential improvement of a riparian environment.

Glyphosate (Gly) and its principal degradation product, the aminomethylphosphonic acid (AMPA) were found in soils from a riparian environment in Argentina. Sixty-five actinobacteria were isolated from these soils, rhizosphere, and plants (Festuca arundinacea and Salix fragilis). The isolate Streptomyces sp. S5 was selected to be used as bioinoculant in a greenhouse test, in which plants, actinobacteria, and their combinations were assessed to bioremediate the riparian soil. The dissipation of both compounds were estimated. All treatments dissipated similarly the Gly, reaching 87-92 % of dissipation. AMPA, dissipation of 38 % and 42 % were obtained by Salix and Festuca, respectively, while they increased to 57 % and 70 % when the actinobacterium was added to each planted system. Regarding the total dissipation, the higher efficiencies for both compounds were achieved by the non-planted soils bioaugmented with the actinobacterium, with 91 % of Gly dissipated and 56 % for AMPA. According to our study, it could be suggested which strategy could be applied depending on the bioremediation type needed. If in situ bioremediation is necessary, the combination of phytoremediation and actinobacteria bioaugmentation could be convenient. On the other hand, if ex situ bioremediation is needed, the inoculation of the soil with an actinobacterium capable to dissipate Gly and AMPA could be the more efficient and easier alternative.

The location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of patients with high-risk NDMM.

Although translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (immunoglobulin heavy chain [IgH] locus) (t(4;14)) is considered high risk in newly diagnosed multiple myeloma (NDMM), only ∼30% to 40% of t(4;14) patients are clinically high risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA sequencing) from 258 t(4;14) (n = 153 discovery, n = 105 replication) and 183 non-t(4;14) NDMM patients with associated clinical data. A landmark survival analysis indicated only ∼25% of t(4;14) patients had an overall survival (OS) <24 months, and a comparative analysis of the patient subgroups identified biomarkers associated with this poor outcome, including translocation breakpoints located in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. Three breakpoints were identified and are designated as: "no-disruption" (upstream of NSD2), "early-disruption" (in the 5' UTR), and "late-disruption" (within the NSD2 gene). Our results show a significant difference in OS based on the location of DNA breakpoints (median OS 28.6 "late-disruption" vs 59.2 "early disruption" vs 75.1 months "no disruption"). These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome in t(4;14) MM patients.

Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma.

Large-scale analyses of genomic data from patients with newly diagnosed multiple myeloma (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory MM (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole-genome sequencing (WGS) data from 418 tumors (386 patients) derived from 6 rrMM clinical trials and compared them with WGS from 198 unrelated patients with ndMM in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), noncoding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNAs; 1qGain, 17pLOH), and double-hit events (Amp1q-ISS3, 1qGain-17p loss-of-heterozygosity). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiD)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain, and 17p loss-of-heterozygosity increased in prevalence from ndMM to lenalidomide resistant (LENR) to pomalidomide resistant (POMR) stages, whereas enrichment of MAML3 along with immunoglobulin lambda (IGL) and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be further evaluated in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.

One-Step and Real-Time Detection of microRNA-21 in Human Samples for Lung Cancer Biosensing Diagnosis.

The rapid diagnosis of cancer, especially in its early stages, is crucial for on-time medical treatment and for increasing the patient survival rate. Lung cancer shows the highest mortality rate and the lowest 5-year survival rate due to the late diagnosis in advanced cancer stages. Providing rapid and reliable diagnostic tools is a top priority to address the problem of a delayed cancer diagnosis. We introduce a nanophotonic biosensor for the direct and real-time detection in human plasma of the microRNA-21-5p biomarker related to lung cancer. The biosensor employs a silicon photonic bimodal interferometric waveguide that provides a highly sensitive detection in a label-free format. We demonstrate a very competitive detectability for direct microRNA-21-5p biomarker assays in human plasma samples (estimated LOD: 25 pM). The diagnostic capability of our biosensor was validated by analyzing 40 clinical samples from healthy individuals and lung cancer patients, previously analyzed by reverse-transcription quantitative polymerase chain reaction (qRT-PCR). We could successfully identify and quantify the levels of microRNA in a one-step assay, without the need for DNA extraction or amplification steps. The study confirmed the significance of implementing this biosensor technique compared to the benchmarking molecular analysis and showed excellent agreement with previous results employing the traditional qRT-PCR. This work opens new possibilities for the true implementation of point-of-care biosensors that enable fast, simple, and efficient early diagnosis of cancer diseases.

The Role of RNA-Binding Proteins in Hematological Malignancies.

Hematological malignancies comprise a plethora of different neoplasms, such as leukemia, lymphoma, and myeloma, plus a myriad of dysplasia, such as myelodysplastic syndromes or anemias. Despite all the advances in patient care and the development of new therapies, some of these malignancies remain incurable, mainly due to resistance and refractoriness to treatment. Therefore, there is an unmet clinical need to identify new biomarkers and potential therapeutic targets that play a role in treatment resistance and contribute to the poor outcomes of these tumors. RNA-binding proteins (RBPs) are a diverse class of proteins that interact with transcripts and noncoding RNAs and are involved in every step of the post-transcriptional processing of transcripts. Dysregulation of RBPs has been associated with the development of hematological malignancies, making them potential valuable biomarkers and potential therapeutic targets. Although a number of dysregulated RBPs have been identified in hematological malignancies, there is a critical need to understand the biology underlying their contribution to pathology, such as the spatiotemporal context and molecular mechanisms involved. In this review, we emphasize the importance of deciphering the regulatory mechanisms of RBPs to pinpoint novel therapeutic targets that could drive or contribute to hematological malignancy biology.

Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma.

The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility.