Search

Abstract: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition of multiple myeloma with few known risk factors. The emergence of mass spectrometry (MS) for the detection of MGUS has provided new opportunities to evaluate its risk factors. In total, 2628 individuals at elevated risk for multiple myeloma were enrolled in a screening study and completed an exposure survey (PROMISE trial). Participant samples were screened by MS, and monoclonal proteins (M-proteins) with concentrations of ≥0.2 g/L were categorized as MS-MGUS. Multivariable logistic models evaluated associations between exposures and MS outcomes. Compared with normal weight (body mass index [BMI] of 18.5 to <25 kg/m2), obesity (BMI of ≥30 kg/m2) was associated with MS-MGUS, adjusting for age, sex, Black race, education, and income (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.21-2.47; P = .003). High physical activity (≥73.5 metabolic equivalent of task (MET)-hours per week vs <10.5 MET-hours per week) had a decreased likelihood of MS-MGUS (OR, 0.45, 95% CI, 0.24-0.80; P = .009), whereas heavy smoking and short sleep had increased likelihood of MS-MGUS (>30 pack-years vs never smoker: OR, 2.19; 95% CI, 1.24-3.74; P = .005, and sleep <6 vs ≥6 hours per day: OR, 2.11; 95% CI, 1.26-3.42; P = .003). In the analysis of all MS-detected monoclonal gammopathies, which are inclusive of M-proteins with concentrations of <0.2 g/L, elevated BMI and smoking were associated with all MS-positive cases. Findings suggest MS-detected monoclonal gammopathies are associated with a broader range of modifiable risk factors than what has been previously identified. This trial was registered at www.clinicaltrials.gov as #NCT03689595., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Prevalence estimates for monoclonal gammopathy of undetermined significance (MGUS) are based on predominantly White study populations screened by serum protein electrophoresis supplemented with immunofixation electrophoresis. A prevalence of 3% is reported for MGUS in the general population of European ancestry aged 50 years or older. MGUS prevalence is two times higher in individuals of African descent or with a family history of conditions related to multiple myeloma. We aimed to evaluate the prevalence and clinical implications of monoclonal gammopathies in a high-risk US population screened by quantitative mass spectrometry., Methods: We used quantitative matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry and EXENT-iQ software to screen for and quantify monoclonal gammopathies in serum from 7622 individuals who consented to the PROMISE screening study between Feb 26, 2019, and Nov 4, 2021, and the Mass General Brigham Biobank (MGBB) between July 28, 2010, and July 1, 2021. M-protein concentrations at the monoclonal gammopathy of indeterminate potential (MGIP) level were confirmed by liquid chromatography mass spectrometry testing. 6305 (83%; 2211 from PROMISE, 4094 from MGBB) of 7622 participants in the cohorts were at high risk for developing a monoclonal gammopathy on the basis of Black race or a family history of haematological malignancies and fell within the eligible high-risk age range (30 years or older for PROMISE cohort and 18 years or older for MGBB cohort); those over 18 years were also eligible if they had two or more family members with a blood cancer (PROMISE cohort). Participants with a plasma cell malignancy diagnosed before screening were excluded. Longitudinal clinical data were available for MGBB participants with a median follow-up time from serum sample screening of 4·5 years (IQR 2·4-6·7). The PROMISE study is registered with ClinicalTrials.gov, NCT03689595., Findings: The median age at time of screening was 56·0 years (IQR 46·8-64·1). 5013 (66%) of 7622 participants were female, 2570 (34%) male, and 39 (<1%) unknown. 2439 (32%) self-identified as Black, 4986 (65%) as White, 119 (2%) as other, and 78 (1%) unknown. Using serum protein electrophoresis with immunofixation electrophoresis, the MGUS prevalence was 6% (101 of 1714) in high-risk individuals aged 50 years or older. Using mass spectrometry, we observed a total prevalence of monoclonal gammopathies of 43% (1788 of 4207) in this group. We termed monoclonal gammopathies below the clinical immunofixation electrophoresis detection level (<0·2 g/L) MGIPs, to differentiate them from those with higher concentrations, termed mass-spectrometry MGUS, which had a 13% (592 of 4207) prevalence by mass spectrometry in high-risk individuals aged 50 years or older. MGIP was predominantly of immunoglobulin M isotype, and its prevalence increased with age (19% [488 of 2564] for individuals aged <50 years, 29% [1464 of 5058] for those aged ≥50 years, and 37% [347 of 946] for those aged ≥70 years). Mass-spectrometry MGUS prevalence increased with age (5% [127 of 2564] for individuals aged <50 years, 13% [678 of 5058] for those aged ≥50 years, and 18% [173 of 946] for those aged ≥70 years) and was higher in men (314 [12%] of 2570) compared with women (485 [10%] 5013; p=0·0002), whereas MGIP prevalence did not differ significantly by gender. In those aged 50 years or older, the prevalence of mass spectrometry was significantly higher in Black participants (224 [17%] of 1356) compared with the controls (p=0·0012) but not in those with family history (368 [13%] of 2851) compared with the controls (p=0·1008). Screen-detected monoclonal gammopathies correlated with increased all-cause mortality in MGBB participants (hazard ratio 1·55, 95% CI 1·16-2·08; p=0·0035). All monoclonal gammopathies were associated with an increased likelihood of comorbidities, including myocardial infarction (odds ratio 1·60, 95% CI 1·26-2·02; p=0·00016 for MGIP-high and 1·39, 1·07-1·80; p=0·015 for mass-spectrometry MGUS)., Interpretation: We detected a high prevalence of monoclonal gammopathies, including age-associated MGIP, and made more precise estimates of mass-spectrometry MGUS compared with conventional gel-based methods. The use of mass spectrometry also highlighted the potential hidden clinical significance of MGIP. Our study suggests the association of monoclonal gammopathies with a variety of clinical phenotypes and decreased overall survival., Funding: Stand Up To Cancer Dream Team, the Multiple Myeloma Research Foundation, and National Institutes of Health., Competing Interests: Declaration of interests DS, DB, MCP are current employees of The Binding Site. MB is a consultant for Takeda and has received honoraria from Takeda, Janssen, and Bristol Myers Squibb (BMS). SH is a current employee, member of the Board of Directors, and holds patents related to The Binding Site. CCM is a consultant for Eli Lilly and Epizyme, is an advisory board member for BMS, has served as a consultant and advisory board member for GlaxoSmithKline (GSK), has received honoraria from Janssen, Karyopharm, and Sanofi; and served as an advisory board member for Karyopharm and Sanofi. PK is a principal investigator of studies for which Mayo Clinic has received research funding from AbbVie, Sanofi, Amgen, GSK, Ichnos, Takeda, Regeneron, and Karyopharm; and has received honoraria from X4 pharmaceuticals, Beigene, Pharmacyclics, Imidex, Clinical Care Options, GSK, Oncopeptides, Cellectar, and Karyopharm. JM is a consultant for Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda. RF is a consultant for AbbVie, Amgen, Bayer, BMS/Celgene, GSK, H3 Therapeutics, Janssen, Juno, Karyopharm, Kite, Merck, Novartis, Oncopeptides, OncoTracker, Pfizer, Pharmacyclics, Regeneron, Sanofi, and Takeda; and is on scientific advisory board of Adaptive Biotechnologies, Caris Life Sciences, OncoMyx, and OncoTracker. GG receives research funds from International Business Machines Corporation and Pharmacyclics and is an inventor on patent applications related to MSMuTect, MSMutSig, MSIDetect, POLYSOLVER, SignatureAnalyzer-GPU and TensorQTL. GG is a founder, consultant and holds privately held equity in Scorpion Therapeutics. CRM has serves as a consultant for JBF Legal and received research funding from GRAIL. IMG has served as a consultant for AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, CurioScience, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, Gene Network Sciences Healthcare, and GSK. IMG's spouse, William Savage is CMO and equity holder at Disc Medicine. All other authors declare no competing interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The hyporheic zone (HZ) is the active ecotone between the surface stream and groundwater, where exchanges of nutrients and organic carbon have been shown to stimulate microbial activity and transformations of carbon and nitrogen. To examine the relationship between sediment texture, biogeochemistry, and biological activity in the Columbia River HZ, the grain size distributions for sediment samples were characterized to define geological facies, and the relationships among physical properties of the facies, physicochemical attributes of the local environment, and the structure and activity of associated microbial communities were examined. Mud and sand content and the presence of microbial heterotrophic and nitrifying communities partially explained the variability in many biogeochemical attributes such as C:N ratio and %TOC. Microbial community analysis revealed a high relative abundance of putative ammonia-oxidizing Thaumarchaeota and nitrite-oxidizing Nitrospirae. Network analysis showed negative relationships between sets of co-varying organisms and sand and mud contents, and positive relationships with total organic carbon. Our results indicate grain size distribution is a good predictor of biogeochemical properties, and that subsets of the overall microbial community respond to different sediment texture. Relationships between facies and hydrobiogeochemical properties enable facies-based conditional simulation/mapping of these properties to inform multiscale modeling of hyporheic exchange and biogeochemical processes.

In this study we aim to explore the potential links between the mechanical properties, micronisation behaviour and surface energy of carbamazepine polymorphs using atomic force microscopy (AFM) measurements of material properties at the nanoscale. Carbamazepine Forms I, II and III were prepared and confirmed using X-ray powder diffraction (XRPD). AFM measurements of indentation hardness, Young's modulus and surface energy were made on the starting material. In addition, the surface energy was measured immediately after micronisation and after storage for four weeks. Carbamazepine polymorphs could be ranked by Young's modulus and hardness. Surface energy measurements showed an increase after micronisation in all cases, and a varying relaxation after storage for four weeks. Form I showed a smaller particle size distribution, indicating more complete micronisation. A promising correlation was observed between the hardness/Young's modulus ratio and the micronisation behaviour, in terms of particle size reduction and surface energy change. The results show potential for the predictive capacity of such an approach, and help to provide a greater understanding of material behaviour and properties during micronisation.

Understanding the movement of the active ingredient in relation to the other formulation components following application is crucial to an overall understanding of herbicide performance. We describe the novel use of time-of-flight secondary ion mass spectrometry (ToF-SIMS) as a tool for following the movement of herbicide formulation components into and across plant cuticles. This technique provides new insights since it provides both high (sub-micron) spatial resolution combined with the chemical specificity associated with organic mass spectrometry. The components studied include the oligomeric ethoxylate surfactants Synperonic A7 and A20 and active ingredient Sulfosate (trimesium glyphosate). The movement of these molecules, both separately and when combined in a simple formulation, into the surface of Prunus laurocerasus leaves and across the isolated plant cuticle was investigated and clear differences in penetration/diffusion behaviour were identified. ToF-SIMS was uniquely able to (simultaneously) spatially resolve all the species involved, including the anion and cation components of the active ingredient. Also, using spectral reconstructions from the imaging raw data streams, the behaviour of individual oligomers within the surfactant distributions, could be assessed. The observations are discussed with reference to the action of surfactants identified in parallel micro-structural studies and the current understanding of herbicide uptake.

The surface properties of the plant cuticle play a crucial role in plant-pathogen interactions and the retention and penetration of agriculturally important chemicals. This paper describes the use of X-ray photoelectron spectroscopy (XPS), time-of-flight secondary-ion mass spectrometry (ToF-SIMS), tapping-mode atomic force microscopy (TM-AFM) and scanning electron microscopy (SEM) to determine surface-specific chemical and material properties of the adaxial surface of Prunus laurocerasus L. leaves. XPS data, derived from the uppermost few nanometres (< 10 nm) of the leaf surface, were consistent with the wax components and functionality known to be present within the waxes. ToF-SIMS provided molecular speciation from the outermost monolayer of the leaf surface, indicating the importance of a family of acetates with chain lengths ranging from C20 to C34. The presence of alkanes with C29 and C31 chain lengths was also confirmed. SEM and TM-AFM topography images revealed a textured granular surface, while simultaneously recorded AFM phase images revealed heterogeneous material properties at the nanoscale. The relevance of these data to plant cuticle development, allelochemistry and agrochemical delivery is discussed.

Although phosphorus has long been considered an important factor in the growth of diverse biota such as bacteria, algae, and zooplankton, insect nutrition has classically focused on dietary protein and energy content. However, research in elemental stoichiometry has suggested that primary producer biomass has similar N:P ratios in aquatic and terrestrial systems, and phosphorus-rich herbivores in freshwater systems frequently face phosphorus-limited nutritional conditions. Therefore, herbivorous insects should also be prone to phosphorus limitation. We tested this prediction by rearing Manduca sexta larvae on artificial and natural (Datura wrightii leaves) diets containing varying levels of phosphorus (approximately 0.20, 0.55, or 1.2% phosphorus by dry weight). For both artificial and natural diets, increased dietary phosphorus significantly increased growth rates and body phosphorus contents, and shortened the time to the final instar molt. Caterpillars did not consistently exhibit compensatory feeding for phosphorus on either type of diet. The growth and body phosphorus responses were not explicable by changes in amounts of potassium or calcium, which co-varied with phosphorus in the diets. Concentrations of phosphorus in D. wrightii leaves collected in the field varied over a range in which leaf phosphorus is predicted to affect M. sexta's growth rates. These results suggest that natural variation in dietary phosphorus is likely to affect the growth rate and population dynamics of M. sexta, and perhaps larval insects more generally., (Copyright 2004 Wiley-Liss, Inc.)

The role of phosphorus (P) in numerous important biological structures, coupled with the observation that P-content of many insect foods is disproportionately low, suggests that P may be a critical nutrient for growing insects - however, the few studies examining the effects of dietary P on insect performance have generally found only weak relationships. This mismatch may be reconciled by understanding the physiological mechanisms by which insects handle P. Here we describe P processing by larvae of Manduca sexta. When given un-manipulated leaves of a common host plant, Datura wrightii, fifth-instar larvae retained about 85% of P consumed; when given P-enriched leaves larvae retained only 25% of P consumed. Analysis of gut concentrations of P at four sites along the digestive tract, and in leaves and feces, indicates that the rectum is the primary site of P transport between the gut and body and that differences in P retention may be accounted for by differential rates of rectal P transport. Larvae given P-enriched leaves also showed an eightfold increase in the concentration of P in the hemolymph, primarily as alpha-glycerophosphate - but only a 12% increase in the concentration of P in body tissues, suggesting that hemolymph plays a central role in storage and buffering of P.