Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia.

Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell-free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele-specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88-mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88-mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.

Real-world data on survival improvement in patients with multiple myeloma treated at a single institution over a 45-year period.

The prognostic landscape of multiple myeloma (MM) has evolved significantly over the last few decades. There are, however, few data measuring such improvement in real-world patients. This study aimed to investigate trends in survival improvement over 45 years, and the associated clinical factors, in an unselected population of patients with MM. Between 1970 and 2015, 1 161 MM patients were included. Patients were classified into three calendar periods (1970-1984, 1985-1999, and 2000-2015), according to the treatment received; polychemotherapy, autologous stem cell transplantation, and novel drugs respectively. We analysed relative survival (RS) to accurately evaluate MM-related death rates after excluding the mortality expected in the general population. RS at five years increased from 27% in 1970-1984 to 38% and 56% in the next two calendar periods respectively. The improvement to survival was greater in the younger population, but it was also observed in elderly patients and those with poor performance status and more advanced disease. Although myeloma is still a non-curable disease, encouraging results have been observed in the last decades. Progress is expected to continue with the use of new generations of anti-myeloma drugs, and will, hopefully, be documented in real-world patients by the appropriate population-based studies.

New treatment strategies for Waldenström macroglobulinemia.

The development of high-throughput technologies has allowed us to characterize the molecular landscape of hematologic neoplasms and identify somatic mutations. As a result, we can now use these technologies to screen for and diagnose neoplastic disease, model risk factors for progression, make treatment decisions, track response to treatment, and design clinical trials. Waldenström macroglobulinemia (WM), which is a lymphoplasmacytic lymphoma, serves as a good example of how genomic data collected at the bench can be applied at the bedside. MYD88 L265P and CXCR4 nonsense and frameshift mutations are the most common recurrent variants observed in patients who have WM, with detection rates of 90% and 40%, respectively. Knowing about these mutations has made it possible to develop agents that target the underlying signaling pathways. In this review, we describe the various treatment strategies for WM and detail the genotype of the malignant WM cell.

Chromatin regulatory genes differentially interact in networks to facilitate distinct GAL1 activity and noise profiles.

Controlling chromatin state constitutes a major regulatory step in gene expression regulation across eukaryotes. While global cellular features or processes are naturally impacted by chromatin state alterations, little is known about how chromatin regulatory genes interact in networks to dictate downstream phenotypes. Using the activity of the canonical galactose network in yeast as a model, here, we measured the impact of the disruption of key chromatin regulatory genes on downstream gene expression, genetic noise and fitness. Using Trichostatin A and nicotinamide, we characterized how drug-based modulation of global histone deacetylase activity affected these phenotypes. Performing epistasis analysis, we discovered phenotype-specific genetic interaction networks of chromatin regulators. Our work provides comprehensive insights into how the galactose network activity is affected by protein interaction networks formed by chromatin regulators.

Immunoparesis defined by heavy/light chain pair suppression in smoldering multiple myeloma shows initial isotype specificity and involves other isotypes in advanced disease.

Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous plasma cell disorder, with a highly variable clinical course. Immunoparesis, defined by total immunoglobulin measurements, has been shown to be an independent risk factor for progression to symptomatic disease. The heavy/light chain (HLC) assay allows precise measurement of the polyclonal immunoglobulin of the same isotype, enabling the evaluation of isotype-matched immunoparesis (IMI). In this study, we prospectively characterized immunoparesis, as determined by HLC measurements, in 53 SMM patients. Severe IMI was present in 51% of patients, while severe IP of uninvolved isotypes (HLC IP) was present in 39%. Most of the patients with severe HLC IP presented with severe IMI, but not the other way around. Isotype specificity of immune suppression was suggested by lower relative values of isotype-matched HLC pairs, both for IgG and IgA SMM. Severe IMI was associated with other risk factors for progression while patients with severe IMI and severe HLC IP showed an even higher risk profile. Both severe IMI and severe IgM HLC IP showed a significantly shorter time to progression. Finally, gene expression analysis demonstrated differences in the bone marrow microenvironment between patients with IMI and IMI plus HLC IP, with an increased expression of genes associated with cytolytic cells. In conclusion, our data supports isotype specificity of early immunoglobulin suppression mechanisms. While suppression of both involved and uninvolved isotypes is associated with risk of progression, the later appears to develop with more advanced disease and could be mediated by different mechanisms.

Centromeric signaling proteins boost G1 cyclin degradation and modulate cell size in budding yeast.

Cell size scales with ploidy in a great range of eukaryotes, but the underlying mechanisms remain unknown. Using various orthogonal single-cell approaches, we show that cell size increases linearly with centromere (CEN) copy number in budding yeast. This effect is due to a G1 delay mediated by increased degradation of Cln3, the most upstream G1 cyclin acting at Start, and specific centromeric signaling proteins, namely Mad3 and Bub3. Mad3 binds both Cln3 and Cdc4, the adaptor component of the Skp1/Cul1/F-box (SCF) complex that targets Cln3 for degradation, these interactions being essential for the CEN-dosage dependent effects on cell size. Our results reveal a pathway that modulates cell size as a function of CEN number, and we speculate that, in cooperation with other CEN-independent mechanisms, it could assist the cell to attain efficient mass/ploidy ratios.

Proteostatic stress as a nodal hallmark of replicative aging.

Aging is characterized by the progressive decline of physiology at the cell, tissue and organism level, leading to an increased risk of mortality. Proteotoxic stress, mitochondrial dysfunction and genomic instability are considered major universal drivers of cell aging, and accumulating evidence establishes clear biunivocal relationships among these key hallmarks. In this regard, the finite lifespan of the budding yeast, together with the extensive armamentarium of available analytical tools, has made this single cell eukaryote a key model to study aging at molecular and cellular levels. Here we review the current data that link proteostasis to cell cycle progression in the budding yeast, focusing on senescence as an inherent phenotype displayed by aged cells. Recent advances in high-throughput systems to study yeast mother cells while they replicate are providing crucial information on aging-related processes and their temporal interdependencies at a systems level. In our view, the available data point to the existence of multiple feedback mechanisms among the major causal factors of aging, which would converge into the loss of proteostasis as a nodal driver of cell senescence and death.

Efficacy and safety of one-day offline extracorporeal photopheresis schedule processing one total blood volume for treating patients with graft-versus-host disease.

BACKGROUND: Extracorporeal photopheresis (ECP) has been increasingly used as a second-line therapy for graft-versus-host disease (GVHD) but there is no consensus regarding the best therapeutic schedule. STUDY DESIGN AND METHODS: Our offline ECP schedule for treating patients with GVHD was retrospectively reviewed. Patients with acute GVHD were treated on 2 days per week for the first 2 weeks, followed by 1 day per week for 2 more weeks. After the first month of treatment, patients received treatment 1 day every 2 weeks for a minimum of 16 ECP procedures. Patients with chronic GVHD were treated on 1 day per week for 4 weeks followed by 1 day every 2 weeks for a minimum of 14 ECP procedures. RESULTS: Our series comprises 21 (45%) patients with acute GVHD and 26 (55%) patients with chronic GVHD who received 667 ECP procedures. A median (interquartile range [IQR]) of 1.0 (1.0-1.12) total blood volume was processed. Patients with acute and chronic GVHD received ECP procedures during a median of 49 (IQR, 14-103) and 180 (IQR, 111-274) days, respectively. Mild citrate-induced symptoms were present in 98 (46%) and 232 (51%) procedures in patients with acute and chronic GVHD, respectively. Overall response rate (ORR) and overall survival (OS) were 57 and 38% (95% confidence interval [CI], 17%-59%), respectively, for patients with acute GVHD. For patients with chronic GVHD, ORR and OS were 77 and 61% (95% CI, 18%-87%), respectively. CONCLUSION: Our new offline ECP schedule for treating patients with acute and chronic GVHD was efficacious and safe.

Decision-making neural circuits mediating social behaviors : An attractor network model.

We propose a mathematical model of a continuous attractor network that controls social behaviors. The model is examined with bifurcation analysis and computer simulations. The results show that the model exhibits stable steady states and thresholds for steady state transitions corresponding to some experimentally observed behaviors, such as aggression control. The performance of the model and the relation with experimental evidence are discussed.

Increased PVR Expression on Bone Marrow Macrophages May Promote Resistance to TIGIT Blockade in Multiple Myeloma.

PURPOSE: TIGIT blockade in our ex vivo models of bone marrow (BM) reduced the number of malignant plasma cells (PCs) in only half of patients with multiple myeloma (MM). Here we wanted to investigate whether increased expression of TIGIT ligands may inhibit T cell immune response promoting resistance to TIGIT blockade. EXPERIMENTAL DESIGN: We first characterized the number and phenotype of BM macrophages in the different stages of disease by multi-parameter flow cytometry. We assessed the effect of TIGIT ligands on PC survival performing experiments with ex vivo BM model and analyzed changes in gene expression by using Nanostring technology and real-time PCR. RESULTS: Frequency of BM macrophages was significantly decreased in MM which was accompanied by changes in their immunophenotype. Moreover, we found a higher number of malignant PCs in ex vivo BM cells cultured onto PVR and nectin-2 compared to control, suggesting that both ligands may support PC survival. In addition, presence of PVR, but not nectin-2, overcame the therapeutic effect of TIGIT blockade or exogenous IL-2. Furthermore, presence of exogenous IL-2 increased TIGIT expression on both CD4+ and CD8+ T cells and, indirectly, PVR on BM macrophages. Consistently, PVR reduced the number of cytotoxic T cells and promoted a gene signature with reduced effector molecules. CONCLUSIONS: IL-2 induced TIGIT on T cells in the BM where increased PVR expression resulted in cytotoxic T cell inhibition promoting PC survival and resistance to TIGIT blockade.

The evolving pattern of the monoclonal protein improves the IMWG 2/20/20 classification for patients with smoldering multiple myeloma.

The 2/20/20 International Myeloma Working Group (IMWG) score is the most employed risk score in clinical practice to evaluate the risk of progression from smoldering multiple myeloma (SMM) to symptomatic multiple myeloma. However, it faces a serious limitation: The risk score is applied at diagnosis and cannot be reapplied. Since a dynamic accurate patient risk assessment for progression is necessary, we aimed to investigate whether the detection of an evolving pattern in serum M-protein (SMP) improves the identification of high-risk patients. Eighty-three patients diagnosed with SMM between 2011 and 2020 were included. Patients were initially classified applying the 2/20/20 IMWG score at baseline and later reclassified depending on the presence of an SMP evolving pattern into six groups. We regrouped the patients into three final risk groups: low-risk, intermediate-risk, and high-risk. The risk of progression at two years for the high-risk group was 88% and all patients had progressed at 4 years. The performance measurements were superior for the new 2/20/20-Evolving score independently for the detection of high-risk patients. We show that the sequential measurement of the SMP is a noninvasive and widely available test that improves the 2/20/20 IMWG risk score.

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

PURPOSE: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. PATIENTS AND METHODS: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. RESULTS: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. CONCLUSIONS: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Color coding in the cortex: a modified approach to bottom-up visual attention.

Itti and Koch's (Vision Research 40:1489-1506, 2000) saliency-based visual attention model is a broadly accepted model that describes how attention processes are deployed in the visual cortex in a pure bottom-up strategy. This work complements their model by modifying the color feature calculation. Evidence suggests that S-cone responses are elicited in the same spatial distribution and have the same sign as responses to M-cone stimuli; these cells are tentatively referred to as red-cyan. For other cells, the S-cone input seems to be aligned with the L-cone input; these cells might be green-magenta cells. To model red-cyan and green-magenta double-opponent cells, we implement a center-surround difference approach of the aforementioned model. The resulting color maps elicited enhanced responses to color salient stimuli when compared to the classic ones at high statistical significance levels. We also show that the modified model improves the prediction of locations attended by human viewers.

A saliency-based bottom-up visual attention model for dynamic scenes analysis.

This work proposes a model of visual bottom-up attention for dynamic scene analysis. Our work adds motion saliency calculations to a neural network model with realistic temporal dynamics [(e.g., building motion salience on top of De Brecht and Saiki Neural Networks 19:1467-1474, (2006)]. The resulting network elicits strong transient responses to moving objects and reaches stability within a biologically plausible time interval. The responses are statistically different comparing between earlier and later motion neural activity; and between moving and non-moving objects. We demonstrate the network on a number of synthetic and real dynamical movie examples. We show that the model captures the motion saliency asymmetry phenomenon. In addition, the motion salience computation enables sudden-onset moving objects that are less salient in the static scene to rise above others. Finally, we include strong consideration for the neural latencies, the Lyapunov stability, and the neural properties being reproduced by the model.

Clinical Implications of Genomic Profile in Waldenström Macroglobulinemia.

With the increasing availability of sequencing techniques and new polymerase chain reaction-based methods, data regarding the genomic profile of Waldenström macroglobulinemia (WM) are being continuously analyzed and reproduced. MYD88 and CXCR4 mutations are highly prevalent in all the stages of WM, including the early IgM monoclonal gammopathy of undetermined significance or a more advanced stage, such as smoldering WM. Thus, there is a need to define genotypes before starting either standard treatment regimens or clinical trials. Here, we review the genomic profile of WM and its clinical implications while focusing on recent advances.

Regulatory and pathogenic mechanisms in response to iron deficiency and excess in fungi.

Iron is an essential element for all eukaryote organisms because of its redox properties, which are important for many biological processes such as DNA synthesis, mitochondrial respiration, oxygen transport, lipid, and carbon metabolism. For this reason, living organisms have developed different strategies and mechanisms to optimally regulate iron acquisition, transport, storage, and uptake in different environmental responses. Moreover, iron plays an essential role during microbial infections. Saccharomyces cerevisiae has been of key importance for decrypting iron homeostasis and regulation mechanisms in eukaryotes. Specifically, the transcription factors Aft1/Aft2 and Yap5 regulate the expression of genes to control iron metabolism in response to its deficiency or excess, adapting to the cell's iron requirements and its availability in the environment. We also review which iron-related virulence factors have the most common fungal human pathogens (Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans). These factors are essential for adaptation in different host niches during pathogenesis, including different fungal-specific iron-uptake mechanisms. While being necessary for virulence, they provide hope for developing novel antifungal treatments, which are currently scarce and usually toxic for patients. In this review, we provide a compilation of the current knowledge about the metabolic response to iron deficiency and excess in fungi.

Sis2 regulates yeast replicative lifespan in a dose-dependent manner.

Application of microfluidic platforms facilitated high-precision measurements of yeast replicative lifespan (RLS); however, comparative quantification of lifespan across strain libraries has been missing. Here we microfluidically measure the RLS of 307 yeast strains, each deleted for a single gene. Despite previous reports of extended lifespan in these strains, we found that 56% of them did not actually live longer than the wild-type; while the remaining 44% showed extended lifespans, the degree of extension was often different from what was previously reported. Deletion of SIS2 gene led to the largest RLS increase observed. Sis2 regulated yeast lifespan in a dose-dependent manner, implying a role for the coenzyme A biosynthesis pathway in lifespan regulation. Introduction of the human PPCDC gene in the sis2Δ background neutralized the lifespan extension. RNA-seq experiments revealed transcriptional increases in cell-cycle machinery components in sis2Δ background. High-precision lifespan measurement will be essential to elucidate the gene network governing lifespan.

Outcomes of Patients with Newly Diagnosed Transplant-Ineligible Multiple Myeloma According to Clinical Trials Enrollment: Experience of a Single Institution.

The proportion of non-transplant-eligible (NTE) newly diagnosed multiple myeloma (NDMM) patients excluded from clinical trials (CTs) and their prognosis is unknown. CT results may not be generalizable to real-world practice due to strict recruitment criteria. We analyzed causes of NTE-NDMM patient exclusion form CTs and their outcomes. A total of 211 NTE-NDMM patients were included. They were divided into three periods: 2003-2007, 2008-2012, and 2013-2017. Overall, 50% received non-trial treatment (NCT), while 50% participated in a CT (20% control group (CG) and 30% experimental group (EG)). Main causes for exclusion from CTs were comorbidities, ECOG > 2, and renal insufficiency. In the first two periods, the CR rate was similar regardless of treatment type, but in the last period, the EG group showed improved CR. Median PFS was similar in the first two periods, with a benefit seen only in the EG in the last period. The median OS was significantly longer in CT-included patients compared to NCT group in the last two periods. Conclusions: The presence of comorbidities and worsened ECOG were the main reasons for CT exclusion. Patients included in CTs had a longer OS than NCT. This OS benefit may be influenced by a selection bias, making it challenging to generalize CT results to real clinical practice.

Corrigendum: Ring attractor bio-inspired neural network for social robot navigation.

[This corrects the article DOI: 10.3389/fnbot.2023.1211570.].

Ring attractor bio-inspired neural network for social robot navigation.

Introduction: We introduce a bio-inspired navigation system for a robot to guide a social agent to a target location while avoiding static and dynamic obstacles. Robot navigation can be accomplished through a model of ring attractor neural networks. This connectivity pattern between neurons enables the generation of stable activity patterns that can represent continuous variables such as heading direction or position. The integration of sensory representation, decision-making, and motor control through ring attractor networks offers a biologically-inspired approach to navigation in complex environments. Methods: The navigation system is divided into perception, planning, and control stages. Our approach is compared to the widely-used Social Force Model and Rapidly Exploring Random Tree Star methods using the Social Individual Index and Relative Motion Index as metrics in simulated experiments. We created a virtual scenario of a pedestrian area with various obstacles and dynamic agents. Results: The results obtained in our experiments demonstrate the effectiveness of this architecture in guiding a social agent while avoiding obstacles, and the metrics used for evaluating the system indicate that our proposal outperforms the widely used Social Force Model. Discussion: Our approach points to improving safety and comfort specifically for human-robot interactions. By integrating the Social Individual Index and Relative Motion Index, this approach considers both social comfort and collision avoidance features, resulting in better human-robot interactions in a crowded environment.