Browse Articles

Assessment of the viability and mechanoresponsiveness of hMSC-TERT printed with bioinert, thermoresponsive hydrogels

Abstract During three-dimensional (3D) bioprinting, the integration of living cells into hydrogel matrices results in complex biophysicochemical interactions between viscosity, shear stress, and temperature, critically influencing the structural and functional integrity of the resulting constructs. This study delves into the short-term biological ramifications of 3D extrusion printing of telomerase-immortalized human mesenchymal stromal cells (hMSC-TERT) embedded in bioinert hydrogels. Pluronic F127 and custom-synthesized poly(2-methyl-2-oxazoline)-block-poly(2-n-propyl-2-oxazine) (POx/POzi) are synthetic, block copolymers that create shear-thinning, physically crosslinked hydrogels that were used for this study. The rheological properties of the cell-free hydrogels and cell-laden bioinks were examined, revealing that they exhibited comparable behavior. Contrary to the original hypotheses, a key finding of this research is the reduction in cell viability (up to 50%) within 24 h post-printing, a trend consistently observed across varying initial conditions. The relative expression levels of the mechanoresponsive genes FOS and PTGS2 were increased, partly due to the suspension and incubation of the cells in both hydrogels. Only FOS was significantly upregulated in some cases because of the printing process after 2 and 4 h of incubation. These insights highlight the potential of using POx/POzi hydrogel as a matrix in 3D bioprinting, particularly for depositing hMSC-TERT into structures with vasculature-mimicking scaffolds or scaffolds designed for bone regeneration.

Impact of treatment escalation on rehospitalization among patients with pulmonary arterial hypertension

Abstract Pulmonary arterial hypertension (PAH) poses a substantial burden, including hospitalizations. This study assessed the impact of treatment escalation on rehospitalization. The Komodo Research Data (10/2015–03/2022) was used to identify adults with ≥ 1 PAH-related hospitalization (index: first hospitalization). Patients on monotherapy pre-index were assigned to the Escalation-to-combination cohort (treatment added ≤ 90 days post-index) or the Monotherapy cohort (no treatment change ≤ 90 days post-index). A sensitivity analysis was conducted among all patients who were treated pre-index. Entropy balancing was used to create cohorts with similar characteristics. All-cause hospitalizations per-patient-per-month (PPPM) during ≤ 12 months post-index were compared across balanced cohorts. A total of 203 and 1252 patients were included in the Escalation-to-combination and Monotherapy cohorts, respectively (mean age: 61 vs. 62 years; 67% vs. 68% female); most received PDE5i monotherapy pre-index (65.3% vs. 75.9%). Post-index, 84.5% of the Escalation-to-combination cohort increased to dual therapy, most commonly PDE5i + ERA (39.4%) and PDE5i + PPA (24.7%). Rehospitalization was lower in the Escalation-to-combination than Monotherapy cohort (incidence rate ratio [95% confidence interval]: 0.69 [0.55–0.90]; p < 0.001); the sensitivity analysis yielded similar results. Treatment escalation was associated with a lower rehospitalization rate, suggesting that earlier escalation and broader use of combination therapy may reduce PAH burden.

Design and analysis of optical encryption for optical transport networks with a rate of 100Gbps based on Mach–Zehnder interferometers

Efficacy and safety of daratumumab in intermediate/high-risk smoldering multiple myeloma: final analysis of CENTAURUS

Abstract Early intervention in smoldering multiple myeloma (SMM) may delay progression to MM. Here, we present the final analysis of the phase 2 CENTAURUS study. In total, 123 patients with intermediate/high-risk SMM were randomized to IV daratumumab 16 mg/kg after a long-intense (n = 41), intermediate (n = 41), or short-intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the long-intense, intermediate, and short-intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P < .0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the long-intense or intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per-protocol treatment. The median duration of study treatment was 44.0 (range, 1.0-91.6), 35.2 (range, 1.9-90.6), and 1.6 (range, 0.1-1.9) months in the long-intense, intermediate, and short-intense arms, respectively. No new safety signals were observed. With extended follow-up (median, ∼7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. This trial was registered at www.ClinicalTrials.gov as #NCT02316106.

Molecular typing of gliomas on the basis of integrin family genes and a functional study of ITGA7

Epcoritamab plus GemOx in transplant-ineligible relapsed/refractory DLBCL: results from the EPCORE NHL-2 trial

Abstract Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes (complete response [CR] rates with standard salvage therapy gemcitabine plus oxaliplatin [GemOx], ∼30%; median overall survival [OS], 10 to 13 months). Patients with refractory disease fare worse (CR rate with salvage therapy, 7%; median OS, 6 months). Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE NHL-2 trial evaluating epcoritamab plus GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL. Patients received 48 mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given once every 2 weeks for 8 doses. The primary end point was overall response rate (ORR). As of 15 December 2023, 103 patients were enrolled (median follow-up, 13.2 months; median age, 72 years). Patients had challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior chimeric antigen receptor T-cell therapy, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR and CR rate were 85% and 61%, respectively. Median duration of CR and OS were 23.6 and 21.6 months, respectively. Common treatment-emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab plus GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT-ineligible R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT04663347.

Study on the moisture permeability of warp-knitted Jacquard shoe upper material based on CFD

Daratumumab: a game changer in early myeloma

Freezing desert soil changes the wind–sand movement pattern

Abstract In the Ulan Buh Desert, which is located in a seasonally frozen region, a frozen soil layer can appear in the winter after the wind erosion of dry sand from the surface of a mobile sand dune, thus altering the wind–sand transport process. To clarify the wind–sand transport pattern after the emergence of a frozen soil layer, this study used wind tunnel experiments to study the variations in the wind erosion rate and sediment transport pattern of frozen and nonfrozen desert soil with different soil moisture contents (1–5%). The results revealed that the relationships of the wind speed, soil moisture content and wind erosion rate are in line with an exponential function, and the wind erosion rate decreases by 6–52% after the desert soil is frozen. When the soil moisture content of the nonfrozen desert and frozen desert soil is 4% and 3%, respectively, the wind erosion rate of the soil can be reduced by more than 65% compared with that of natural dry sand (soil moisture content of 0.28%), i.e., the wind erosion rate can be effectively reduced. The sediment transport rate of nonfrozen desert soil decreases with increasing height, with an average ratio of approximately 65% for saltation. The sediment transport rate of frozen desert soil first increases but then decreases with increasing height, with an average ratio of approximately 80% for saltation. When sand particles hit the source of frozen desert soil, the interaction between particles and bed surface is dominated by the process of impact and rebound, so that more particles move higher, and some sand particles move from creep to saltation. In summary, freezing has an inhibitory effect on the wind–sand activity of desert soil, and freezing makes it easier for sand to move upwards.

Appearances deceive: unmasking mantle cell lymphoma with prolymphocytic morphology

Acoustic monitoring with miniature drones shows reduced Myotis bat occurrence with altitude and drone movement

Abstract Our understanding of aeroecology is hampered by the challenge of sampling the air column, especially for nocturnal species like bats that forage high in the airspace. Nonetheless, monitoring endangered bat populations is vital for conservation efforts. Drones (unoccupied aerial vehicles) offer a relatively safe, cost-effective, and non-intrusive option for studying aerial wildlife. Here, we present a method for measuring bat distribution in the airspace using miniature drones (Mavic Mini 3 Pro) that are small enough to have negligible impacts on the bats themselves. We investigate how habitat, drone altitude, and drone movement influence bat sampling efficiency. A hovering drone detected more bats per minute than a moving drone for the EPNO complex (Eptesicus fuscus and Lasionycteris noctivagans) and all bats. Thus, we recommend the use of hovering point counts for surveying bats via drone. The Myotis complex (M. septentrionalis, M. lucifugus, and M. leibii) was more frequently present at lower altitudes over the sampled range (0–60 m). We conclude that bat taxa differentially occupy sectors of the air column, and that bat density in the airspace can be efficiently monitored by miniature drones.

Zhu H-H, Hu J, Lo-Coco F, Jin J. The simpler, the better: oral arsenic for acute promyelocytic leukemia. <i>Blood</i>. 2019;134(7):597-605.

Network structure of common mental health problems and life satisfaction in a Japanese population

Abstract Poor life-satisfaction, feelings of loneliness, depression, and anxiety are commonly reported in the Japanese general population. The aim of this study was to examine the network structure of these common mental health problems in a Japanese sample and to explore differences between males and females. Participants (N = 476; 235 males, 241 females) were recruited from a Japanese general population and completed questionnaires to measure levels of depression, anxiety, loneliness, and life satisfaction. A psychometric network analysis was conducted using a Gaussian Graphical Model, and a network comparison test (NCT) was performed to evaluate overall consistency and differences in global network connectivity. The network analysis identified problems relaxing, sad mood, feelings of isolation, and poor life satisfaction as central nodes in the overall network. The NCT revealed no significant differences between the male and female networks in the global network structure as well as connectivity. However, the strength values for restlessness and tiredness were significantly higher in the network for males than in the network for females. There were no differences in the global network structure and connectivity of mental health psychopathology between males and females. Problems relaxing, feelings of depression, being isolated from others, and poor life satisfaction contribute to poor mental health and may be potential intervention targets.

Targeting cell-surface VISTA expression on allospecific naïve T cells promotes tolerance

Abstract The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be limited by graft-versus-host disease (GVHD). T-cell activation is a key factor in GVHD progression. Costimulatory signals can be counterbalanced by coinhibitory signals such as the checkpoint molecule VISTA (V-domain immunoglobulin-containing suppressor of T-cell activation)/programmed death-1 homolog that restrains activation and maintains donor T-cell quiescence. A single dose of anti-VISTA monoclonal antibody (mAb) prevents acute GVHD lethality in multiple models. Naïve donor T cells express moderate VISTA levels, which transiently increase in allo-HSCT recipients in association with T-cell receptor signaling, leading to heightened susceptibility to anti-VISTA mAb–mediated depletion, in contrast to donor T cells transferred to syngeneic recipients. Anti-VISTA mAb donor T-cell depletion was compatible with rapamycin but incompatible with peritransplant tacrolimus GVHD prophylaxis. Targeting VISTA exclusively on host cells or donor CD8+ T cells was not protective against GVHD lethality. Instead, anti-VISTA mAb–mediated deletion of alloreactive donor T cells depended on targeting a third (non-T) cell type. Further mechanistic studies indicated that donor T cells concurrently exposed to anti-VISTA mAb in vivo but not preincubated in vitro before adoptive T-cell transfer were eliminated via Fc receptor (FcR)-mediated phagocytosis. In a lymphoma challenge model, a graft-versus-lymphoma (GVL) effect was fully retained when anti-human VISTA mAb exclusively targeted donor CD4+ T cells, and was delayed but mostly retained when unseparated donor T cells were infused. In a xenogeneic GVHD model, anti-human VISTA mAb reduced donor T-cell expansion, VISTA T-cell expression levels, and recipient lethality. Together, these data support a novel clinical translational pathway in which acute GVHD lethality can be mitigated without negating the GVL effect.

Improved YOLO for long range detection of small drones

Paraspinal mass and lower extremity weakness in a patient with thalassemia

Functional organotypic human lymph node model with native immune cells benefits from fibroblastic reticular cell enrichment

Acoustic modes in M67 cluster stars trace deepening convective envelopes

Abstract Acoustic oscillations in stars are sensitive to stellar interiors1. Frequency differences between overtone modes—large separations—probe stellar density2, whereas differences between low-degree modes—small separations—probe the sound-speed gradient in the energy-generating core of main-sequence Sun-like stars3, and hence their ages. At later phases of stellar evolution, characterized by inert cores, small separations are believed to lose much of their power to probe deep interiors and become proportional to large separations4,5. Here we present evidence of a rapidly evolving convective zone as stars evolve from the subgiant phase into red giants. By measuring acoustic oscillations in 27 stars from the open cluster M67, we observe deviations of proportionality between small and large separations, which are caused by the influence of the bottom of the convective envelope. These deviations become apparent as the convective envelope penetrates deep into the star during subgiant and red giant evolutions, eventually entering an ultradeep regime that leads to the red-giant-branch luminosity bump. The tight sequence of cluster stars, free of large spreads in ages and fundamental properties, is essential for revealing the connection between the observed small separations and the chemical discontinuities occurring at the bottom of the convective envelope. We use this sequence to show that combining large and small separations can improve estimations of the masses and ages of field stars well after the main sequence.

Tumor burden quantified by soluble B-cell maturation antigen and metabolic tumor volume determines myeloma CAR-T outcomes

Abstract Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a breakthrough treatment for relapsed and refractory multiple myeloma (RRMM). However, these products are complex to deliver, and alternative options are now available. Identifying biomarkers that can predict therapeutic outcomes is crucial for optimizing patient selection. There is a paucity of data evaluating the utility of both serum soluble B-cell maturation antigen (sBCMA) levels and metabolic tumor volume (MTV) at baseline in patients with RRMM undergoing CAR-T therapy. We identified a cohort of 183 patients with available serum to measure sBCMA and/or pretreatment MTV, derived from positron emission tomography–computed tomography scans obtained per standard of care. Expectedly, high pretreatment levels of sBCMA correlated with other established markers of tumor burden (eg, bone marrow plasma cells and β2 microglobulin) and inflammation and were highly prognostic for CAR-T–related toxicities and inferior progression-free survival (PFS). High MTV values were also associated with shorter PFS and inferior overall survival. The poor correlation observed between these 2 measures prompted evaluation of those with discordant results, identifying that those with low sBCMA and high MTV frequently had low/absent BCMA expression on plasma cells and suboptimal response. Our findings highlight the potential utility of sBCMA and MTV to facilitate more personalized treatment strategies in the management of RRMM eligible for BCMA-directed CAR-T.

Association of MPO levels with cardiometabolic disease stratified by atherosclerotic cardiovascular risk and intensity of therapy in a workforce population

Abstract Cardiometabolic risk increases cardiovascular (CVD), chronic kidney (CKD) and non-alcoholic fatty liver (NAFLD) disease risk. High myeloperoxidase (MPO) levels identify individuals at risk for CVD. We whether elevation of MPO associated with kidney and liver disease risk in subgroups stratified by ASCVD risk and intensity of therapy. Adjusted logistic models assessed the associations of MPO with markers of kidney disease (estimated glomerular filtration rate) and liver fibrosis (NAFLD score &gt; 0.676 or Fibrosis-4 [FIB-4] score &gt; 2.67) across ASCVD risk (low &lt; 7.5%; intermediate 7.5% to &lt; 20%; high ≥ 20%). This retrospective study comprised 20,772 participants in an employer-sponsored health assessment. High MPO associated with impaired kidney function with low (OR 2.2, 95% CI 1.6–3.7) and intermediate (OR 2.0, 95% CI 1.3–3.5) ASCVD risk, and with high FIB-4 or NAFLD scores in low (OR 2.4, 95% CI 1.2–4.7), intermediate (OR 3.1, 95% CI 2.0–6.0), and high (OR 3.8, 95% CI 2.9–7.4) ASCVD risk groups. High MPO was associated with markers of CKD and liver fibrosis in low to intermediate ASCVD risk and treated groups. These findings demonstrate the commonality of cardiometabolic biomarkers across multiple organs.   Prospective studies are warranted to assess whether high MPO levels identify persons at risk for CKD and liver fibrosis who may benefit from preventive strategies.