Low Expansion Research Articles

Critical risk factors of electric road uptake on motorways: a Swedish Delphi study

ABSTRACT This paper presents the results of a ranking-type Delphi study on the critical risk factors for the adoption of an electric road system (e-road) for trucks on the main motorways in Sweden. The investment cost of such a system is high, necessitating an upfront evaluation of the adoption risk factors to reduce the likelihood of budget overruns and project delays. Participating Swedish e-road experts (N = 52) from the public sector, private sector, and academia identified 32 unique risk factors, which were divided into five categories. The three most critical risk factors, as ranked by the experts, were ‘low expansion rate,’ ‘low utilization rate,’ and ‘lengthy public-sector evaluation.’ Overall, market and financial risks were ranked as more important than institutional, technological, and sustainability risks. This study has important implications for policymakers in countries considering e-road adoption.

Enhanced shear strength of Cu/AlN/Cu gradient materials with continuous and quasi‐continuous interfacial structures

AbstractIn the electronic industry, the composite of copper (Cu) and aluminum nitride (AlN) is widely used, but obtaining Cu/AlN/Cu functionally gradient materials (Cu/AlN/Cu FGMs) in a single step using traditional laminated sintering processes has proven challenging due to significant differences in their physical properties. To address this issue, molybdenum (Mo), with a high melting point and low expansion, was involved in creating a continuous gradient structure with AlN and a quasi‐continuous interfacial structure with Cu. The continuous interfacial structure of Mo/AlN gradient materials was obtained by hot pressing at 1650°C. Subsequently, the quasi‐continuous interfacial structure of Cu/Mo heterogeneous metal joints with high shear strength was achieved by utilizing the diffusion welding method at 700–950°C. The results indicated that the optimum shear strength of Cu/AlN/Cu FGMs is around 90 MPa. However, Cu/AlN/Cu FGMs with different diffusion interlayers failed in different ways when shear occurred, which greatly depends on the phase compositions at the joint. The challenges are overcome by utilizing Mo to construct the continuous and quasi‐continuous interfaces, resulting in Cu/AlN/Cu FGMs with improved shear properties.

Effects of rapeseed protein addition on soybean protein-based textured protein produced by low-moisture extrusion: Changes in physicochemical attributes, structural properties and barrel flow behaviors

This study investigated the potential of rapeseed protein as a novel alternative protein source in meat analogs produced by extrusion cooking technology. To study the substitutability of rapeseed protein to soybean protein, the addition ratios of rapeseed protein to soybean protein in the extrusion experiment were 0:50, 10:40, 20:30, 30:20, 40:10 and 50:0 (w/w), respectively. The results showed that adding 0–20% rapeseed protein not only decreased the specific mechanical energy and mass flow rate of the mixture during extrusion, but also enhanced the hardness and chewiness of the extrudates while reducing their elasticity and resilience. In addition, increasing the amount of rapeseed protein may lead to decreased expansion characteristics, internal pore structure, and water absorption rate of the extrudates, as well as a decrease in brightness and an increase in redness on the surface. Weibull model could well describe the rehydration behavior for dynamic fitting of the extrusion rehydration process. Moreover, with the increase of rapeseed protein substitution, the content of disulfide bonds, and the proportion of relatively ordered protein secondary structures with high stability increased, and the degree of protein denaturation decreased. Besides, the degree of starch gelatinization reduced and the thermal stability of extrudates improved. Interaction analysis indicated that disulfide bonds are the primary force maintaining protein-mediated interactions in the extrudates. The incorporation of rapeseed protein shortened the mean residence time of molten feedstock and shifted the flow state to plug flow. Overall, our investigation suggests that within low levels of addition (≤20%, w/w), rapeseed protein has the potential to partially substitute for the soybean protein-based textured proteins. High substitution levels or complete substitution are not feasible due to the relatively low expansion and rehydration rates.

Calcium silicate composited nano-Si anode with low expansion and high performance for lithium-ion batteries

Calcium silicate composited nano-Si anode with low expansion and high performance for lithium-ion batteries

Recent progress in low‐swellable polymer‐based smart photonic crystal sensors

AbstractLow‐swelling polymers (LSPs) generally refer to materials with a low solvent absorption ratio or volume expansion rate at swelling equilibrium. LSPs with exceptional responsiveness could be upgraded to smart sensors with structural color self‐reporting by bridging photonic crystals (PCs). Based on the regulation of swelling to effective refractive index, lattice spacing, the order‐disorder arrangement of nanostructures, and incident/detection angle, the structural color feedback of smart photonic crystal sensors (SPCSs) can quantitatively and visually reveal the stimulus, which greatly promotes the interdisciplinary development of nanophotonic technology in the fields of chemical engineering, materials science, engineering mechanics, biomedicine, environmental engineering, etc. Herein, to clarify the role of the photonic structures and polymer molecules in high‐performance SPCSs, LSP‐based SPCSs are summarized and discussed, including general swelling mechanisms, color change strategies, structural design, and typical functional applications. It aims to figure out the combination rule between PC structures and LSPs, optimize the design of PC structures, and expound the corresponding structural color sensing mechanisms, inspiring the fabrication of next‐generation SPCSs. Finally, perspectives on future structural design and sensing applications are also presented. It is believed that SPCSs are multifunctional nanophotonic tools for the interdisciplinary development of numerous engineering fields in the future.

Phenotypic, Transcriptomic and Proteomic Characteristics of CAR T-Cell Dysfunction Are Associated with Inferior CAR T-Cell Expansion and Treatment Failure in r/r B-NHL

Introduction: Despite the curative potential of CAR T-cells, a significant number of patients fail to respond or relapse early. Recently, we and others showed that early expansion failure, and particularly CAR T-cell levels at day 7, are strong predictors for treatment resistance (Blumenberg et al, Blood Supplement 2022; Locke et al, Blood Adv 2020). Here we dissected early characteristics of CAR T-cell dysfunction based on immune checkpoint expression, transcriptomic signatures and cytokine profiles and investigated their link to CAR T-cell expansion failure and patient outcome of CD19-targeted CAR T-cell therapy. Methods: Patients with r/r B-NHL who underwent treatment with axi-cel or tisa-cel between January 2019 and November 2021 in the third- or later-line setting at the LMU in Munich were included (n=55). EDTA-anticoagulated peripheral blood and serum was collected. CD19 CAR and immune checkpoint expression (IC; PD-1, TIM-3, LAG-3 and CD224) was assessed by multiparameter flow cytometry on day 14 after CAR T-cell infusion. A next-generation targeted single-cell proteogenomics approach (BD Rhapsody TM) to analyze the transcriptome of distinct CAR T-cell subpopulations on day 7 and day 28 after CAR T-cell infusion. A total of 92 human immuno-oncology related proteins were simultaneously measured using the Olink® Immuno-Oncology panel on day 14 after infusion. Signatures of CAR T-cell dysfunction have been compared between patients with low (loEx) or high (hiEx; < vs ≥ 19 CAR T-cells/µl at day 7 post infusion)CAR T-cell expansion and were put into context of clinical outcome measures. Results: CAR T-cell levels at day 7 were inversely correlated to co-expression of PD-1 (r = -0.4923, p = 0.0011, n = 41), TIM-3 (r = -0.3634, p = 0.0195, n = 41) and LAG-3 (r = -0.5412, p = 0.0003, n = 41) on CAR T-cells at day 14, suggestive of an association of early expansion failure and dysfunction of CAR T-cells. Indeed, loEx (n=26) showed higher frequencies of CAR T-cells coexpressing several IC, including LAG-3 + (p=0.0036), LAG-3 +PD-1 + (p = 0.0048), or LAG-3 +TIM-3 + (p = 0.0065) compared to hiEx (n=15) on day 14 after transfusion. Conversely, we detected higher frequencies of non-dysfunctional CAR T-cell phenotypes negative for several IC, such as CD244 +PD-1 -TIM-3 - (p = 0.0006), CD244 +LAG-3 -PD-1 -TIM-3 - (p = 0.001) and CD244 +LAG-3 +PD-1 -TIM-3 - (p = 0.011) in hiEx. Next, we applied uniform manifold approximation and projection (UMAP) data to examine the surface expression of IC on CAR T-cells at day 14 post-infusion according to treatment response. Unsupervised clustering revealed a higher abundance of CAR T-cell clusters positive for several IC (CD244 +LAG-3 -PD-1 +TIM-3 +) in NR (n = 16) compared to R (n = 23). By contrast, CAR T-cell clusters containing CAR T-cells expressing no IC were more abundant in R compared to NR. In addition, we found significantly increased levels of a highly dysfunctional CAR T-cell phenotype positive for all four IC in NR compared to R at day 14 post infusion (p = 0.0178, n = 46). When specifically comparing the transcriptome of CAR T-cells between NR (n = 6) and R (n = 6), immune inhibitory and exhaustion-related genes were upregulated in NR, such as GZMK, KLRC1 and NR4A2 (figure 1, cluster 1). Conversely, CAR T-cells in R overexpressed genes related to T-cell effector function and cell differentiation, such as TIMP-1, TNFDF10 and MYC (figure 1, cluster 0). Consistent with these findings, a multiplexed proteomics assay for immunomodulatory serum factors in day 14 samples revealed an upregulation of proteins linked to an immune inhibitory and inflamed milieu in patients with highly dysfunctional CAR T-cells (e.g., sPD-L1 and sLAG-3, p = 0.0235 and p = 0.0264, respectively, n = 46) as well as in non-responding patients (e.g., sPD-L1 and IL-6, p = 0.0036 and p = 0.0053, respectively, n = 55). Conclusion: We were able to characterize a phenotypic, transcriptomic and proteomic signature of CAR T-cell dysfunction in post-infusion samples of both patients experiencing CAR T-cell expansion failure as well as lack of radiographic response. Our data show that treatment failure might be predicted not only by CAR T-cell kinetics but also by early assessment of the CAR T-cell phenotype, transcriptome and secretome, and thus enables identification of patients in need of salvage treatment.

The monetary policy pass-through mechanism: Is the search-for-yield incentive at work?

The paper investigates the possible mechanism behind the link between monetary policy and bank lending/risk-taking behaviors. Using a sample of Vietnamese commercial banks during 2007–2019, we find that the impact on bank output associated with monetary policy shocks is attributable to banks’ incentives to search for yield. Concretely, if interest rates remain lower amid monetary expansions, banks are likely to expand their lending activities more aggressively and take more risks to offset their reduced revenues. Moreover, this crucial supply-side effect is also at work for the bank liquidity creation channel of monetary policy transmission. Accordingly, we document that demotivated banks appear to undermine the impact of monetary policy on the core function of banks in creating liquidity to the real economy. Our finding is robust against a series of alternative monetary policy indicators, different bank output measures, multiple search-for-yield proxies, and substitute econometric methodologies. In sum, as the monetary policy pass-through transmission through the key banking channels is found due to banks’ own decisions, monetary authorities need to take this underlying mechanism into account when setting their monetary policy.

CFT thermal 2-point function

This is a short review of our recent work [B. Bajc and A. R. Lugo, arXiv:2212.13639 [hep-th]] with some new original results. We numerically calculate the conformal two point correlation function of operators with arbitrary scale dimension up to order [Formula: see text] in the low temperature expansion. We analytically compute its large scale dimension limit up to the same order.

Low thermal expansion and weak hygroscopicity of Y2-xZrxMo3-xPxO12

A new functional ceramic material Y2-xZrxMo3-xPxO12 was prepared by solid sintering method in the study. In order to further decrease the phase transition temperature of Y2Mo3O12 and improve its water absorption, a new low-expansion material of Y2-xZrxMo3-xPxO12 was prepared by replacing Y3+/Mo6+ ions in Y2Mo3O12 with Zr4+/P5+ ions. The hygroscopicity and thermal expansion of the material were further analyzed. Y2-xZrxMo3-xPxO12 (0.4 ≤ x ≤ 0.8) was an orthomorphic phase with space group Pbcn at room temperature and little crystal water existed in the lattice. With the increase in doped ions, the hygroscopicity of Y2Mo3O12 was weakened significantly. When the substitution content reached x = 0.4, Y1.6Zr0.4Mo2.6P0.4O12 realized the coefficient of thermal expansion (CTE) of 1.82 × 10−6 K−1 in the temperature range from 300 K to 700 K and showed the nearly non-hygroscopicity and low thermal expansion (LTE) at room temperature.

Comprehensive scrutiny of surface mechanical parameters of graphyne-based materials for metal-ions and metal-air batteries applications: A perspective and a hybrid atomistic-continuum model

Graphyne family, as a low-dimensional carbon allotrope, is utilized for metal-ion and –air batteries as the anode and cathode materials due to their unique characteristics. These novel carbon nanomaterials can provide more theoretical storage capacity than graphene, while their specific surface mechanical parameters and vibrational frequencies can influence battery performance. However, there needs to be clear information that can explain the effects of these parameters on battery efficiency. In this respect, the influences of the surface elasticity, residual stress, density, vibrational modes, and frequencies of α, β, and γ-graphyne circular monolayers on anode and cathode materials have been investigated in current research using the hybrid molecular dynamics simulation and modified classical continuum mechanics methods. Concerning metal-ion batteries, the results disclose that the suitability sequence for anode materials can be expressed as γ-graphyne > graphene > β-graphyne > α-graphyne monolayers. In the case of metal-air batteries, the competence sequence for cathode materials is in the order of γ-graphyne > β-graphyne ∼ graphene > α-graphyne monolayers. Therefore, γ-graphyne with suitable storage capacity, low volume expansion, good surface elasticity, low surface residual stress, and appropriate specific surface area is the promising anode and cathode material for metal-ion and -air batteries, respectively.

PVO-based reversible data hiding using bit plane segmentation and pixel expansion

The existing pixel value ordering (PVO)-based reversible data hiding (RDH) approaches have been investigated; however, the functions of these techniques are weak when embedded in rough image regions. Therefore, a novel PVO-RDH method is proposed herein. This method performs ‘bit-plane segmentation low bit-plane weighted-pixel expansion’ on an image, which improves the original PVO-RDH method’s embedding performance in rough image regions. Pixel expansion increases the number of image chunks, thereby improving the maximum embedding capability of the carrier image. After preprocessing, the expanded picture is chunked using the original PVO-RDH strategy, and the maximum value in the chunk is modified via prediction. In contrast to the results of previous studies, the current experimental findings indicate that the proposed strategy improves the average PSNR by at least 2.97 dB when the embedding data are 10000 bit. The experimental findings show a significant improvement in the embedding volume and PSNR of the proposed algorithm.

Phase 2 Study of CD19 CAR T Cells with a Fully Human Binder for Large B-Cell Lymphoma in Relapse or Progression after a Murine Binder-Bearing CD19 CAR T-Cell Therapy

BACKGROUND T cells engineered with a CD19-targeted chimeric antigen receptor (CD19 CAR T cells) have revolutionized the treatment of high-risk, relapsed, or refractory large B-cell lymphoma (LBCL), but durable responses are only achieved in 30-40% of patients (pts). Outcomes are dismal in case of disease recurrence after CD19 CAR T-therapy; in this situation we have previously reported low efficacy and limited duration of response after a second infusion of the same CD19 CAR T-cell product (Gauthier, Blood, 2022). We observed that repeat CD19 CAR T-cell infusions were impaired by CD8+ T-cell responses against murine amino acid sequences located in the single chain variable fragment (scFv) of the CAR, which led to rapid immune rejection of CAR T cells. We hypothesized that CAR T cells engineered with a fully human scFv could circumvent anti-murine scFv immune responses in pts previously exposed to murine scFv-bearing CAR T cells. We report our phase 2 clinical trial results investigating treatment with fully human scFv-bearing CD19 CAR T cells (JCAR021) in R/R LBCL pts with relapsed or progressive disease after murine scFv-bearing CD19 CAR T-cell therapy. METHODS Pts with R/R LBCL were enrolled at the Fred Hutchinson Cancer Center on a phase II study (NCT03103971). Key eligibility criteria included: i) relapsed disease after complete response (CR) to prior CD19-targeted non-JCAR021 CAR T-cell therapy or persistent disease after partial response to prior CD19-targeted non-JCAR021 CAR T-cell therapy; ii) CD19-positive disease since completing the prior CD19-targeted CAR T-cell therapy. Pts received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days. Cytokine release syndrome (CRS) and neurotoxicity (NT) were graded according to the Lee 2014 criteria and CTCAE v4.03 criteria, respectively. Disease response was evaluated at day +28 after JCAR021 infusion per PET-CT Lugano criteria. The planned sample size and CAR T-cell dose were n=27 and 7x10 6 CAR T cells/kg, respectively. RESULTS Pt characteristics, and outcomes are shown in the Table. All eight screened pts were enrolled, received LD, and JCAR021 infusion. Median age at enrollment was 63 (range: 41-77). Prior to lymphodepletion, 4 pts (50%) had bulky disease (largest lesion ≥5cm). All pts had extranodal disease. We observed elevated LDH prior to lymphodepletion in 6 pts (75%). Median prior lines of therapy was 5 (range: 3-7). Prior CD19 CAR T-cell product type was lisocabtagene maraleucel, n=4 (50%); axicabtagene ciloleucel, n= 3 (37%); or tisagenlecleucel, n=1. Response to the prior CD19 CAR T-cell therapy was CR in 5 pts (62%) and PR in 3 pts (38%). Median time from the first CAR T-cell infusion to relapse or progression was 165 days (range 49-434). Median time from the first CAR T-cell infusion to JCAR021 infusion was 304 days (range: 202-603). JCAR021 was administered at the dose of 7x10 6 (n=6, 75%) or 2x10 6 CAR T-cells/kg (n=2, 25%; dose reduction due to grade 5 NT in subject #6). We observed all-grade CRS in 4 pts (50%; grade 1, n=2; grade 2, n=2 not requiring vasopressors) and NT in 1 patient (dose limiting toxicity, grade 5 NT from intracerebral hemorrhage with concurrent acute kidney injury and toxic encephalopathy). At day+28 responses were seen in 3 of 8 pts (37%; CR, n=2; PR, n=1), all of whom received 7x10 6 CAR T-cells/kg. Two pts in CR after JCAR021 had bulky disease and elevated LDH prior to LD. In both pts, the prior CD19 CAR T-cell therapy had induced CR lasting ≥ 6 months. In the two evaluable responders (death in CR, n=1), we observed disease relapse or progression within 3 months. Median overall survival was 105 days (95%CI, 92-NA). We measured expansion of JCAR021 CAR T-cells in all pts. Exploratory analyses showed lower in vitro CAR T-cell expansion during manufacturing (fold expansion of CD8+ CAR T-cells, p<0.001) and lower in vivo CAR T-cell expansion (peak CD8+ CAR-T, p=0.002; AUC day0-28, p=0.01; JCAR021 dose, 7x10 6/kg) compared to pts receiving JCAR021 as their first CD19 CAR-T product (CAR-naïve cohort). CONCLUSION In LBCL pts with disease relapse or progression after a first CD19 CAR T-cell therapy, we observed low response rates and lack of durable responses after treatment with the fully human scFv-bearing product JCAR021, prompting early study termination. Lower CAR T-cell expansion during manufacturing in CAR-exposed pts suggest pre-existing T-cell dysfunction as a potential mechanism of failure.

Contrasting Features of T-Cell Expansion in Classical Hodgkin Lymphoma: Tumor Microenvironment Vs. Peripheral Blood and before Vs. during Anti-PD1 Treatment

Introduction The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant CD4+ and CD8+ T-cells and only few Hodgkin-Reed-Sternberg cells (HRSC). Despite their low abundance, HRSC comprise the neoplastic cell population that intensively interacts with cells of the TME. Understanding these interactions is crucial to the further development of immune checkpoint blockade (ICB) based treatment options. Clinical trials have shown high efficacy of ICB with anti-PD1 antibodies in relapsed HL and more recently promising results of anti-PD1 antibodies in combination with conventional chemotherapy were reported in the first-line setting. (NIVAHL trial, NCT03004833) In solid cancers, anti-PD1 ICB was shown to revert tumor-induced exhaustion of CD4+ and CD8+ T-cells, thereby enabling T-cell activation and a tumor-directed immune response. Since HL differs in many aspects from non-lymphoid tumors due to e.g. loss of HLA-expression, the exact mechanisms of action of ICB in HL is not fully understood and T-cell expansion after anti-PD1 first-line treatment not yet studied. Methods To characterize T-cell activation at different timepoints and to investigate a possible T-cell mediated immune response in HL, we analyzed T-cell Receptor (TCR) repertoires of the NIVAHL study cohort before (tissue: n=90; blood: n=9) and during anti-PD1 treatment (tissue: n=4; blood: n=9). The final cohort comprised additional TCR repertoires of in-house tissue biopsies of treatment-naïve HL (n=18), relapsed HL after chemotherapy (HL-R; n=18)) and publicly available TCR repertoires of the blood of treatment-naïve HL (n=11), HL-R (n=20) and HL-R patients during anti-PD1 treatment (n=20). (Cader et al. Nat Med. 2020 Sep;26(9):1468-1479) TCR repertoires of in-house reactive lymph nodes (n=8, healthy control) and breast cancer (BC; n=6, positive control) patients served as controls for T-cell activation in the tissue, publicly available TCR repertoires of CMV- (n=22, healthy control) and CMV+ otherwise healthy (n=9, positive control) people as controls in the blood. (De Neuter et al. Genes Immun. 2019 Mar;20(3):255-260) TCR repertoires were sequenced by Adaptive Biotechnologies. For each sample, TCR sequences with the same amino acid sequence were aggregated by the sum of their counts. We computed three measures to describe T-cell expansion: debiased Simpson's Clonality (dSC), Percentage of Singletons (PoS), and clonal expansion. Singletons have recently been defined as TCR sequences detected only once in a given sample. Clonal expansion is computed as the percentage of TCR sequences that increase their frequency in a patient from one timepoint to a following by ≥ 2. Results In tissue biopsies, treatment-naïve HL showed a significantly lower dSC compared to treatment-naïve BC and significantly higher dSC compared to RLN from healthy controls. No significant differences could be observed comparing HL with different treatments (during anti-PD1 vs. after chemotherapy) and treatment-naïve HL vs. HL during anti-PD1 treatment. HL and HL-R biopsies showed a significantly lower clonal expansion of Non-Singletons than BC tumors. In peripheral blood, healthy controls, treatment-naïve HL and HL patients during anti-PD1 treatment showed significantly lower dSC in their CD4+ T-cells compared to CMV+ controls and also compared to HL-R patients. We identified significantly higher dSC in CD8+ T-cells compared to CD4+ T-cells in the blood of HL patients before and during any treatment and in relapsed HL. During anti-PD1 treatment, CD8+ T-cells showed a significantly higher clonal expansion of Non-Singletons than CD4+ T-cells in HL-R and a similar but not significant trend in HL. All observed differences in dSC were significant for the PoS too, but as expected by their respective definitions with an opposing pattern (i.e. dSC high = PoS low). Discussion We did not observe features of intratumoral T-cell expansion in primary HL samples, early during anti-PD1 treatment or at relapse after chemotherapy, suggesting that within the HL tissue, T-cell expansion is hampered. However, patterns of T-cell expansion differed between TME and the peripheral blood, where we observed features of CD8+ T-cell clonal expansion, already prior to any treatment. In summary, our findings suggest a possible anti-tumor immune response of CD8+ T-cells in the peripheral blood of HL patients, that is not found in the TME.

Neuropeptide Y Attenuates Aging-Induced Bone Marrow Niche Defects and Rejuvenate Aged Hematopoietic Stem/Progenitor Cells

Aging-associated defects in hematopoiesis are linked to declining in hematopoietic stem cell (HSC) self-renewal and multilineage differentiation capacity. The bone marrow (BM) microenvironment/niche has been suggested to influence HSC aging. However, the factors/mechanisms whereby the BM niche mediates hematopoietic stem and progenitor (HSPC) aging are poorly understood. We recently discovered that neuropeptide Y (NPY) plays a crucial role in HSPC trafficking by regulating the BM vascular gateway function (PMCID: PMC5707149). NPY is one of the most abundant neurotransmitters released in the BM by sympathetic nerve fibers. In this study, we found that the aging-induced deficit of NPY levels in the BM plays a critical role in niche defects and HSPC aging by impairing the molecular pathways involved in regulating oxidative stress, senescence, and stemness. The measurement of NPY levels in the BM of young (3-4 months) and aged (18-23 months) mice showed lower NPY levels in aged mice than in young mice (2.2-fold), which was associated with a decrease in mesenchymal stem cells (MSC) (2-fold, p=0.008) and endothelial cells (EC) (1.5-fold, p<0.05) numbers in the BM. In addition, we found that circulating NPY levels decline in the older human population (65-83 years) than in young/ middle age (23-55 years) individuals (1.5-fold, p=0.01). We hypothesized if aging-induced NPY deficit contributes to BM niche defects and HSPC aging, then NPY supplementation may attenuate/revert these processes. To explore this possibility, we administered exogenous NPY in aged mice (100ng/mouse) for 15 consecutive days and evaluated HSPC and niche cells. NPY supplementation in aged mice (18-23 months) substantially reverted aged HSPC phenotype, including NPY decreased the accumulation of HSC-enriched SLAM LSK (Lin-Sca-1+c-Kit+CD48-CD150+) in the BM (1.8-fold, p<0.05) and increased the HPC clonal expansion (1.9-fold, p<0.05) measured by flow cytometry and CFU-C assay, respectively. Competitive BM transplantation studies using donor cells from young, aged, or NPY-treated aged mice into lethally irradiated syngeneic mice showed myeloid biased repopulation from aged mice donor cells than young mice donor cells, and that was attenuated in NPY-treated aged mice donor cells (33%, p=0.003). In addition, NPY substantially reverted aging-related reduction in BM MSC (CD45-Ter119-CD31-Nestin+PDGFR+CD51+) and EC (CD45-Ter119-CD31+VE-cadherin+) numbers, and BM MSC clonal expansion (2-fold, p<0.05) as measured by CFU-F assay. To further validate NPY's role in the aged BM niche and HSPC function, we used NPY gene overexpressing and knockout (KO) mouse models. Compared to wild-type (WT) aged mice, NPY overexpressing aged mice showed a substantial increase in BM niche MSC numbers (1.4-fold, P=0.03) and improved HSPC clonal expansion (2.5-fold, P=0.002). In contrast, 16-18 months old NPY KO mice showed enhanced aging than aged WT mice, reflected by fewer MSC counts and lower HSPC clonal expansion (MSC: 1.6-fold, and CFU-F: 1.5-fold, <0.05). Oxidative stress and senescence are the hallmarks of aging. To examine if NPY attenuates HSPC aging by controlling oxidative and senescence, we measured reactive oxygen species (ROS) and senescence in SLAM-LSK of young, aged, and NPY-treated aged mice using CellROX and anti-p16 antibodies, respectively. The SLAM-LSK from aged mice showed higher expression of ROS (9-fold, p=0.03) and p16 than young mice (1.7-fold). However, ROS and p16 expression were decreased in NPY-treated aged mice (ROS: 2-fold, and p16: 1.3-fold, p<0.05). To identify the molecular pathways involved in NPY-mediated attenuation of HSPC aging, we performed RNA sequencing analysis of SLAM-LSK cells. Aged mice SLAM LSK showed impaired expression of genes involved in pathways regulating antioxidant defense, DNA damage repair and stemness than in young mice SLAM LSK. However, NPY treatment in aged mice substantially restored these pathways in SLAM LSK. In conclusion, our studies suggest that an aging-induced deficit in NPY levels in the BM is a crucial lesion contributing to niche defects and HSPC aging. Thus, NPY supplementation or protection of NPY-producing nerve fibers in the BM can attenuate/restore aging-induced niche damage and rejuvenate aged HSPC.

Undetectable MRD Status in Patients with R/R CLL/SLL with Stable Disease after Lisocabtagene Maraleucel Treatment: Exploratory Analysis of the TRANSCEND CLL 004 Study

Background:For patients (pts) with R/R CLL/SLL after failure of Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i)-based treatment, there is no established standard of care and therefore there is a high unmet therapeutic need. The phase 1/2 TRANSCEND CLL 004 study (NCT03331198) investigated the efficacy and safety of lisocabtagene maraleucel(liso-cel) monotherapy, an autologous CD19-directed CAR T cell therapy, in pts with heavily pretreated R/R CLL/SLL and ≥ 2 previous lines of therapy, including a BTKi. The primary analysis demonstrated durable CR/CR with incomplete marrow recovery (CRi) per 2018 International Workshop on CLL (iwCLL 2018) criteria, high undetectable MRD (uMRD; 10 −4 sensitivity) rates, and a manageable safety profile in pts who received liso-cel (Siddiqi T, et al. Lancet 2023). All evaluable responders (CR/CRi/PR) achieved blood uMRD status. Among evaluable pts with stable disease (SD), uMRD status was associated with longer median PFS (6.4 months) versus MRD-positive (MRD+) status (PFS, 2.8 months). This exploratory analysis aimed to better understand potential variables associated with achieving uMRD in pts who had SD with liso-cel. Methods: Among 96 pts in the full efficacy set who were treated with liso-cel at dose level 1 (50 × 10⁶ CAR + T cells) or 2 (100 × 10⁶ CAR + T cells), 80 pts were evaluable for peripheral blood MRD. Peripheral blood MRD status was assessed by next-generation sequencing (NGS; clonoSEQ) assay; uMRD was defined as < 10 −4 (< 1 CLL cell per 10,000) at 1 or more postinfusion time points. Additional exploratory analysis leveraged sample-level MRD results defined by total clonal cells/total nucleated cells assessed by NGS. Cellular kinetics were analyzed in peripheral blood samples by qPCR to detect the liso-cel transgene. Correlative analysis studies of baseline markers of tumor burden (sum of the product of diameters; CD19 + cells/μL; percent CLL cells in bone marrow biopsies or aspirates) with liso-cel expansion were evaluated by MRD status. Statistical analyses were performed using the Wilcoxon signed-rank test. Results:Of the 80 pts who were evaluable for peripheral blood MRD, 34 had a best overall response of SD, 19 of whom achieved uMRD and 15 who were MRD+. Greater liso-cel expansion parameters (median maximum expansion and area under the curve from 0-28 days postinfusion) were observed in all pts, including those with SD, who achieved uMRD versus MRD+ status ( P < 0.0001), suggesting that higher liso-cel expansion after infusion was associated with achievement of uMRD independent of iwCLL 2018 response. Regardless of baseline tumor burden, pts with higher liso-cel expansion achieved uMRD after liso-cel treatment. A positive association between tumor burden and liso-cel expansion in pts with SD and uMRD was also observed. In contrast, pts with SD who were MRD+ had lower liso-cel expansion and trends of higher baseline disease burden. Liso-cel expansion in pts with SD and uMRD clustered with the responders, who all achieved uMRD status (in those evaluable for MRD). Notably, 4 pts with SD and uMRD had a durable disease control of > 22 months. We wanted to further understand the relationship between uMRD and durable disease control. Given that the median PFS of pts with SD and uMRD was 6 months, we evaluated the association between tumor burden and liso-cel expansion in pts who had a PFS of ≤ 6 months or > 6 months. Although no clear association was observed with liso-cel expansion and tumor burden within these 2 groups, 4 out of 5 pts with SD and uMRD with longer disease control (PFS > 6 months) had a > 98% decrease in sample-level MRD from Month 1 to Month 3. In contrast, in pts with SD and uMRD with PFS ≤ 6 months, 5 out of 7 pts had a > 70% increase in sample-level MRD from Month 1 to Month 3. Conclusions:In this exploratory analysis of pts with R/R CLL who had SD by iwCLL 2018 criteria after liso-cel treatment, greater liso-cel expansion, regardless of baseline tumor burden, correlated with blood uMRD status. Additionally, those with a PFS > 6 months achieved deeper clearance of blood sample-level MRD within 3 months of treatment versus those with a PFS ≤ 6 months, suggesting that MRD kinetics may identify pts with SD who can achieve durable disease control despite not achieving a response per iwCLL 2018 criteria. Further investigation is needed to better understand which subsets of pts with CLL who had SD may derive clinical benefit from liso-cel.

Thermoplastic extrusion technology as a tool for adding value to brewer's by-products

Brewer's by-products show high nutritious potential to be reintegrated into the food chain. Nevertheless, their high moisture, microbiological instability, and heterogeneity pose enormous challenges. This study investigated thermoplastic extrusion to repurpose large amounts of the two main brewery by-products: brewer's spent grains (BSG) and brewer's spent yeast (BSY). A mixture design was used to compose ten blends with different proportions of dried-BSG, BSY, and corn grits, maximizing the use of BSG up to 70 g/100 g. Extruder parameters were fixed. PLS regression was applied to evaluate the effects of blend composition on the characteristics of the extruded products. Thermoplastic extrusion shows feasibility in transforming large volumes of by-products into value-added products. Blends with high insoluble fiber, protein, and moisture contents resulted in extrudates with high protein concentration, low expansion, and high density. The results of this exploratory work can be used for product optimization by choosing nutritional, technological, and commercial targets to create innovative, healthy, and sustainable food products that meet consumer demands.

Fabrication of SnO2 micron-rods embedding in 3D composite of graphene oxide@MWNTs as high-performance anode for lithium-ion batteries

Tin dioxide-based anode materials have attracted extensive attention in lithium-ion batteries due to their high specific capacity. However, the low intrinsic conductivity and volume expansion of commercial SnO2, as well as the aggregation due to snation result in electrodes that are highly susceptible to crush during the cycling process. Here, SnO2@GO@MWNTs complex consisting of rod-like SnO2 with micron-size uniformly embedded in the multi-walled carbon nanotubes (MWNTs) and multilayer graphene oxide (GO) was constructed via a simple ultrasonic mixing method, and was employed as the anode materials of lithium-ion batteries. This composite electrode showed excellent cycling performance, exhibiting a high reversible capacity of 1242.6 mAh·g−1 after 280 cycles (at 200 mA·g−1), and excellent rate performance at current densities of 1000 mA·g−1 and 2000 mA·g−1, with high specific capacity of 770.5 mAh·g−1 and 640.1 mAh·g−1, respectively. The excellent electrochemical performance was attributed to the fact that the framework structure formed by GO and MWNTs effectively mitigates the volume expansion of rod-shaped SnO2 while improving its electrical conductivity, and the micron-sized rods shape alleviates the aggregation of particles due to the partial tinisation of SnO2.

Outcome analysis and assessment of the lower pole expansion following breast augmentation with ergonomic implants: Optimizing results with patient selection based on 5-year data

Silicone implants have gone through adaptations to improve esthetic outcomes. With the progress of technology, including gel rheology, different properties have been introduced. Ergonomic style implants (ESI) feature enhanced rheological properties and provide a shaped contour with a round base. This study investigated outcomes for ESI in breast augmentation concerning lower pole stretching (LPS) and implant stability and describes an algorithm to assist in decision-making. A total of 148 patients (296 breasts) underwent breast augmentation with ESI; this procedure was indicated in patients with good skin quality and <6cm between the nipple-areola complex and the inframammary fold. The mean patient age was 29.6 years (range: 19-39), and 93 patients (62.8%) underwent primary breast augmentation with demi/full projection (average volume of 245 cc [175-375 cc]). Axillary incision and subfascial pocket were indicated in 115 (77.7%) and 72 (48%) cases, respectively. Average LPS values were 32.2% (24.91mm) and 10.86% (9.42mm) at up to 10 days and 10 days to 12 months postprocedure, respectively. Patients were followed for a mean of 29.9±26.4 months (range: 6-66). Complication rates per breast and per patient were 5% and 10%, respectively, and included subcutaneous banding in the axilla (1.6%), implant displacement (1.2%), and wound dehiscence (0.8%). No cases of infection, seroma, or rippling complications were observed. The present decision-making algorithm summarizes the process involved in breast augmentation using ESI and is intended to help standardize decisions. With correct planning, long-lasting outcomes can be achieved due to favorable interactions between ESI and the patient's tissues.

Metal–Organic Framework‐Derived SnS2/C/CNT as Anode Material for Lithium‐Ion Batteries with High Capacity and Stability

SnS2 is considered to be an ideal replacement material for graphite anodes, and has attracted much attention from scientific researchers due to its high theoretical capacity and low cost. However, the application of SnS2 is restricted by its low electrical conductivity and severe volume expansion during cycle. Herein, SnS2/C/CNT material is obtained by high temperature vulcanization and solvent heat treatment with Sn metal–organic framework (MOF) as precursor, while the carbon skeleton of the MOF is preserved. The carbon nanotubes(CNTs) are evenly distributed across the MOF‐derived C frameworks to create a carbon network that improves the electrical conductivity of SnS2 and inhibits its volume expansion. Therefore, the modified SnS2/C/CNT anode has still maintained a high discharge capacity of 954.2 mAh g−1 after 100 cycles at the current density of 200 mA g−1 with a high capacity retention rate of 89.3%. It also exhibits excellent rate capability (739.8, 669.1, and 575.8 mAh g−1 for 0.5, 1, and 2 A g−1). In addition, the SnS2/C/CNT material also shows good electrochemical performance even without conductive additives.

Nanostructured Porous Polymer with Low Volume Expansion, Structural Distortion, and Gradual Activation for High and Durable Lithium Storage.

Organic compounds exhibit great potential as sustainable, tailorable, and environmentally friendly electrode materials for rechargeable batteries. However, the intrinsic defects of organic electrodes, including solubility, low ionic conductivity, and restricted electroactivity sites, will inevitably decrease the cycling life and capacity. We herein designed and prepared nanostructured porous polymers (NPP) with a simple one-pot method to overcome the above defects. Theoretical calculations and experimental results demonstrate that the as-synthesized NPP exhibited low volume expansion, molecular-structural distortion, and a gradual function activation process during cycling, thus exhibiting superior, high, and durable lithium storage. The gradual molecular distortion during the lithium storage processes provides more redox-active sites for Li storage, increasing the Li-storage capacity. Ex situ spectrum studies reveal the redox reaction mechanism of Li storage and demonstrate a gradual activation process during the repeated charging/discharging until the full storage of 18 Li ions is achieved. Additionally, a real-time observation on the NPP anode by in situ transmission electron microscope reveals a slight volume expansion during the repeating lithiation and delithiation processes, ensuring its structural integrity during cycling. This quantitative work for high-durability lithium storage could be of immediate benefit for designing organic electrode materials.