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Deconvoluting the vibrations and harmonics in solid-solid interfaces is crucial for designing materials with improved performance, durability, and functionality. The measured vibrating microcantilever signal in the dynamic atomic force microscopy (AFM) encompasses a multitude of distinct signatures reflecting a diverse array of material properties. Nevertheless, uncertainties persist in decoding these signatures, primarily arising from the interplay between attractive and repulsive forces. Consequently, it is challenging to correlate the generated harmonics within the solid-solid interfaces with the imaged phase and topography of materials, as well as the occasional observed contrast reversal. In this study, the vibration harmonics produced at solid-solid interfaces are correlated, linking them to short-range nano-mechanical characteristics through a comprehensive blend of theory, simulation, and experimental methods. These findings shed light on the roots of harmonic generation and contrast reversals, opening avenues for designing innovative materials with customized properties., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Low levels and function of natural killer (NK) cells are associated with increased coronavirus disease 2019 (COVID-19) severity. NK cell immunotherapy may improve immune function to reduce infection severity. We conducted a first-in-human, open-label, phase 1, dose-escalating (100 × 10 6 , 300 × 10 6 , or 900 × 10 6 cells) study of a single dose of DVX201, a cord-blood-derived allogeneic NK cell therapy, in hospitalized patients with COVID-19. Participants were followed for 28 days. The maximum allowed steroid dose for eligibility was up to 0.5 mg/kg prednisone (or equivalent) daily. We enrolled nine participants, 3 per dose level. Eight participants had ≥1 comorbidity associated with increased COVID-19 severity, three of whom had a hematologic malignancy. Infusions were well tolerated, with no treatment-related adverse events. There was no evidence of inflammatory complications related to infusions. Peripheral blood NK cells generally increased after infusion, peaking by day 7. The median time from infusion to discharge was 2 days (range: 1-13). Two patients (both with acute lymphoblastic leukemia) were readmitted with recurrent COVID-19. This trial demonstrates the safety of allogeneic NK cell immunotherapy as a potential antiviral. Larger controlled trials are needed to establish efficacy., Competing Interests: A.T., C.S., J.C., J.B., and C.S.D. are employees of and have equity in Deverra Therapeutics. C.S.D. is also an employee of Coeptis Therapeutics. J.A.H. received research funding from Deverra Therapeutics for the conduct of this trial, has received research funding from Allovir, Gilead, Takeda, and Merck, and served as a consultant for Moderna, Allovir, Gilead, SentiBio, Modulus, Takeda, and CSL Behring., (© 2024 The Author(s).)

Introduction: The endocannabinoid system (ECS) is a widespread neurotransmitter system. A key characteristic of the ECS is that there are multiple endogenous ligands (endocannabinoids). Of these, the most extensively studied are arachidonoyl ethanolamide (AEA) and 2-arachidonoyl-glycerol (2-AG), both act as agonists at the cannabinoid CB 1 receptor. In humans, three CB 1 variants have been identified: hCB 1 , considered the most abundant G protein-coupled receptor in the brain, alongside the less abundant and studied variants, hCB 1a and hCB 1b . CB 1 exhibits a preference for coupling with inhibitory G i/o proteins, although its interactions with specific members of the G i/o family remain poorly characterized. This study aimed to compare the AEA and 2-AG-induced activation of various G protein subtypes at CB 1 . Furthermore, we compared the response of human CB 1 (hCB 1 , hCB 1a , hCB 1b ) and explored species differences by examining rodent receptors (mCB 1 , rCB 1 ). Materials and Methods: Activation of individual G protein subtypes in HEK293 cells transiently expressing CB 1 was measured with G protein dissociation assay utilizing TRUPATH biosensors. The performance of the TRUPATH biosensors was evaluated using Z-factor analysis. Pathway potencies and efficacies were analyzed using the operational analysis of bias to determine G protein subtype selectivity for AEA and 2-AG. Results: Initial screening of TRUPATH biosensors performance revealed variable sensitivities within our system. Based on the biosensor performance, the G protein subtypes pursued for further characterization were G i1 , G i3 , G oA , G oB , G Z , G 12 , and G 13 . Across all pathways, AEA demonstrated partial agonism, whereas 2-AG exhibited full or high-efficacy agonism. Notably, we provide direct evidence that the hCB 1 receptor couples to G 12 and G 13 proteins. Our findings do not indicate any evidence of G protein subtype selectivity. Similar observations were made across the human receptor variants (hCB 1 , hCB 1a , hCB 1b ), as well as at mCB 1 and rCB 1 . Discussion: There was no evidence suggesting G protein subtype selectivity for AEA and 2-AG at CB 1 , and this finding remained consistent across human receptor variants and different species.

Synovial Sarcoma (SySa) is an aggressive soft tissue sarcoma that accounts for 5 - 10% of all soft tissue sarcomas. Current treatment involves radiation and radical surgery including limb amputation, highlighting the urgent need to develop targeted therapies. We reasoned that transcriptional rewiring by the fusion protein SS18-SSX, the sole oncogenic driver in SySa, creates specific vulnerabilities that can be exploited for treatment. To uncover genes that are selectively essential for SySa, we mined The Cancer Dependency Map (DepMap) data to identify genes that specifically impact the fitness of SySa compared to other tumor cell lines. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) was one of the strongest dependencies both in vitro as well as in vivo . TAK-981, a clinical-stage small molecule SUMO2 inhibitor potently inhibited growth and colony-forming ability. Strikingly, transcriptomic studies showed that pharmacological SUMO2 inhibition with TAK-981 treatment elicited a profound reversal of a gene expression program orchestrated by SS18-SSX fusions. Of note, genetic or pharmacological SUMO2 inhibition reduced global and chromatin levels of the SS18-SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark that plays an important role in SySa pathogenesis. Taken together, our studies identify SUMO2 as a novel, selective vulnerability in SySa. Since SUMO2 inhibitors are currently in Phase 1/2 clinical trials for other cancers, our findings present a novel avenue for targeted treatment of synovial sarcoma., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing interests or conflicts of interest related to this work.

Itaconate is one of the most studied immunometabolites produced by myeloid cells during inflammatory response. It mediates a wide range of anti-inflammatory and immunoregulatory effects and plays a role in a number of pathological states, including autoimmunity and cancer. Itaconate and its derivatives are considered potential therapeutic agents for the treatment of inflammatory diseases. While immunoregulatory effects of itaconate have been extensively studied in vitro and using knockout mouse models, less is known about how therapeutic administration of this metabolite regulates inflammatory response in vivo. Here, we investigate the immunoregulatory properties of exogenous administration of itaconate and its derivative dimethyl itaconate in a mouse model of lipopolysaccharide-induced inflammation. The data show that administration of itaconate or dimethyl itaconate controls systemic production of multiple cytokines, including increased IL-10 production. However, only dimethyl itaconate was able to suppress systemic production of IFNγ and IL-1β. In contrast to in vitro data, administration of itaconate or dimethyl itaconate in vivo resulted in systemic upregulation of IL-6 in the blood. Electrophilic stress due to itaconate or dimethyl itaconate was not responsible for IL-6 upregulation. However, inhibition of succinate dehydrogenase with dimethyl malonate also resulted in elevated systemic levels of IL-6 and IL-10. Taken together, our study reports a novel effect of exogenous itaconate and its derivative dimethyl itaconate on the production of IL-6 in vivo, with important implications for the development of itaconate-based anti-inflammatory therapies., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Metastasis remains the leading cause of cancer deaths worldwide and lung cancer, known for its highly metastatic progression, remains among the most lethal of malignancies. Lung cancer metastasis can selectively spread to multiple different organs, however the genetic and molecular drivers for this process are still poorly understood. Understanding the heterogeneous genomic profile of lung cancer metastases is considered key in identifying therapeutic targets that prevent its spread. Research has identified the key source for metastasis being clusters of cells rather than individual cancer cells. These clusters, known as metastatic cancer cell clusters (MCCCs) have been shown to be 100-fold more tumorigenic than individual cancer cells. Unfortunately, access to these primary drivers of metastases remains difficult and has limited our understanding of their molecular and genomic profiles. Strong evidence in the literature suggests that differentially regulated biological pathways in MCCCs can provide new therapeutic drug targets to help combat cancer metastases. In order to expand research into MCCCs and their role in metastasis, we demonstrate a novel, proof of principle technology, to capture MCCCs directly from patients' whole blood. Our platform can be readily tuned for different solid tumor types by combining a biomimicry-based margination effect coupled with immunoaffinity to isolate MCCCs. Adopting a selective capture approach based on overexpressed CD44 in MCCCs provides a methodology that preferentially isolates them from whole blood. Furthermore, we demonstrate a high capture efficiency of more than 90% when spiking MCCC-like model cell clusters into whole blood. Characterization of the captured MCCCs from lung cancer patients by immunofluorescence staining and genomic analyses, suggests highly differential morphologies and genomic profiles. This study lays the foundation to identify potential drug targets thus unlocking a new area of anti-metastatic therapeutics., Competing Interests: Jeffrey K. Allen is the President/Founder of TumorGen and holds shares of the company as well as Peter Teriete who is the Co-Founder/Scientific Advisor of TumorGen and also holds shares of the company. Please note that holding these interests does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Kouhmareh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Nanomechanical sensors, due to their small size and high sensitivity to the environment, hold significant promise for various sensing applications. These sensors enable rapid, highly sensitive, and selective detection of biological and biochemical entities as well as mass spectrometry by utilizing the frequency shift of nanomechanical resonators. Nanomechanical systems have been employed to measure the mass of cells and biomolecules and study the fundamentals of surface science such as phase transitions and diffusion. Here, we develop a methodology using both experimental measurements and numerical simulations to explore the characteristics of nanomechanical resonators when the detection entities are absorbed on the cantilever surface and quantify the mass, density, and Young's modulus of adsorbed entities. Moreover, based on this proposed concept, we present an experimental method for measuring the mass of molecules and living biological entities in their physiological environment. This approach could find applications in predicting the behavior of bionanoelectromechanical resonators functionalized with biological capture molecules, as well as in label-free, nonfunctionalized micro/nanoscale biosensing and mass spectrometry of living bioentities.

Objectives: The potential benefit of transcarotid artery revascularization (TCAR) over transfemoral carotid artery stenting (tfCAS) has been studied in the perioperative period with lower rates of stroke and death; however, data on mid-term outcomes are limited. We aimed to evaluate 3-year outcomes after TCAR and tfCAS and determine the primary predictors of 30-day and 1-year mortality following TCAR., Methods: Data from the Vascular Quality Initiative for patients undergoing TCAR or tfCAS from January 2016 to December 2022 were analyzed. 1:1 propensity score matching using the nearest-neighbor method was used to adjust baseline demographics and clinical characteristics. Kaplan-Meier survival analysis and Cox Proportional Hazard Regression were used to evaluate long-term outcomes. Iterative stepwise multiple logistic regression analysis and Cox Proportional Hazard Regression were used to identify predictors of 30-day and 1-year mortality, respectively, based upon preoperative, intraoperative, and postoperative factors., Results: A total of 70 237 patients were included in analysis (TCAR=58.7%, tfCAS=41.3%). Transcarotid artery revascularization patients were older and had higher rates of comorbid conditions and high-risk medical and anatomic features than tfCAS patients. Propensity score matching yielded 22 322 pairs with no major differences between groups except that TCAR patients were older (71.6 years vs 70.8 years). At 3 years, TCAR was associated with a 24% reduction in hazard of death compared with tfCAS (hazard ratio [HR]=0.76, 95% confidence interval [CI]=0.71-0.82, p<0.001), for both symptomatic and asymptomatic patients. This survival advantage was established in the first 6 months (HR=0.59, 95% CI=0.53-0.62, p<0.001), with no difference in mortality risk from 6 months to 36 months (HR=0.95, 95% CI=0.86-1.05, p=0.31). Transcarotid artery revascularization was also associated with decreased hazard for 3-year stroke (HR=0.81, 95% CI=0.66-0.99, p=0.04) and stroke or death (HR=0.81, 95% CI=0.76-0.87, p<0.001) compared with tfCAS. The top predictors for 30-day and 1-year mortality were postoperative complications. The primary independent predictor was the occurrence of postoperative stroke., Conclusions: Transcarotid artery revascularization had a sustained mid-term survival advantage associated over tfCAS, with the benefit being established primarily within the first 6 months. Notably, our findings highlight the importance of postoperative stroke as the primary independent predictor for 30-day and 1-year mortal., Clinical Impact: The ongoing debate over the superiority of TCAR compared to tfCAS and CEA has been limited by a lack of comparative studies examining the impact of pre-operative symptoms on outcomes. Furthermore, data are scarce on mid-term outcomes for TCAR beyond the perioperative period. As a result, it remains uncertain whether the initial benefits of stroke and death reduction observed with TCAR over tfCAS persist beyond one year. Our study addresses these gaps in the literature, offering evidence to enable clinicians to assess the efficacy of TCAR for up to three years. Additionally, our study seeks to identify risk factors for postoperative mortality following TCAR, facilitating optimal patient stratification., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acute leukemia is a particularly problematic collection of hematological cancers, and, while somewhat rare, the survival rate of patients is typically abysmal without bone marrow transplantation. Furthermore, traditional chemotherapies used as standard-of-care for patients cause significant side effects. Understanding the evolution of leukemia to identify novel targets and, therefore, drug treatment regimens is a significant medical need. Genomic rearrangements and other structural variations (SVs) have long been known to be causative and pathogenic in multiple types of cancer, including leukemia. These SVs may be involved in cancer initiation, progression, clonal evolution, and drug resistance, and a better understanding of SVs from individual patients may help guide therapeutic options. Here, we show the utilization of optical genome mapping (OGM) to detect known and novel SVs in the samples of patients with leukemia. Importantly, this technology provides an unprecedented level of granularity and quantitation unavailable to other current techniques and allows for the unbiased detection of novel SVs, which may be relevant to disease pathogenesis and/or drug resistance. Coupled with the chemosensitivities of these samples to FDA-approved oncology drugs, we show how an impartial integrative analysis of these diverse datasets can be used to associate the detected genomic rearrangements with multiple drug sensitivity profiles. Indeed, an insertion in the gene MUSK is shown to be associated with increased sensitivity to the clinically relevant agent Idarubicin, while partial tandem duplication events in the KMT2A gene are related to the efficacy of another frontline treatment, Cytarabine.

Two juvenile red foxes (Vulpes vulpes) were euthanased because of severe nervous signs and paralysis. Detailed postmortem examinations were carried out with bacteriology, histology, and Clostridium botulinum toxin screening, which confirmed botulism as the cause of the clinical signs., (© Wildlife Disease Association 2024.)