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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physicians choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

Arc-based traffic assignment models (TAMs) are a popular framework for modeling traffic network congestion generated by self-interested travelers who sequentially select arcs based on their perceived latency on the network. However, existing arc-based TAMs either assign travelers to cyclic paths, or do not extend to networks with bidirectional arcs (edges) between nodes. To overcome these difficulties, we propose a new modeling framework for stochastic arc-based TAMs. Given a traffic network with bidirectional arcs, we replicate its arcs and nodes to construct a directed acyclic graph (DAG), which we call the Condensed DAG (CoDAG) representation. Self-interested travelers sequentially select arcs on the CoDAG representation to reach their destination. We show that the associated equilibrium flow, which we call the Condensed DAG equilibrium, exists, is unique, and can be characterized as a strictly convex optimization problem. Moreover, we propose a discrete-time dynamical system that captures a natural adaptation rule employed by self-interested travelers to learn about the emergent congestion on the network. We show that the arc flows generated by this adaptation rule converges to a neighborhood of Condensed DAG equilibrium. To our knowledge, our work is the first to study learning and adaptation in an arc-based TAM. Finally, we present numerical results that corroborate our theoretical results.

Abstract Eastern equine encephalitis virus (EEEV) is the most virulent alphavirus that infects humans, and many survivors develop neurological sequelae, including paralysis and intellectual disability. Alphavirus spike proteins comprise trimers of heterodimers of glycoproteins E2 and E1 that mediate binding to cellular receptors and fusion of virus and host cell membranes during entry. We recently identified very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as cellular receptors for EEEV and a distantly related alphavirus, Semliki Forest virus (SFV). Here, we use single-particle cryo-electron microscopy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR ligand-binding domain and found that EEEV and SFV interact with the same cellular receptor through divergent binding modes. Our studies suggest that the ability of LDLR-related proteins to interact with viral spike proteins through very small footprints with flexible binding modes results in a low evolutionary barrier to the acquisition of LDLR-related proteins as cellular receptors for diverse sets of viruses.

The strength and plasticity of 10B38 boron containing cold heading steel under different high temperature condi⁃ tions were studied using high-temperature tensile testing method. The results showed that the tensile strength decreased significantly from 124. 8 MPa to 22. 9 MPa at temperatures ranging from 700 to 950 ℃； At 950 to 1 150 ℃， the tensile strength was 12. 7 to 25. 5 MPa. In terms of thermoplastic properties， the cross-sectional shrinkage rate at 700-750 ℃ was 56%-72%； When the temperature was between 800 and 1 050 ℃， the cross-sectional shrinkage rate was ≥ 75%； When the temperature was between 1 050 and 1 150 ℃， the cross-sectional shrinkage rate was greater than 65%. Based on the above experimental data， the strength of the secondary cooling water in continuous casting was optimized from a specific water content of 1. 35 L/kg to a specific water content of 1. 25 L/kg. After optimization， the crack index of the continuous casting slab was significantly reduced. The dynamic CCT curves of 10B38 boron containing cold heading steel were mea⁃ sured， The experimental results showed that when the cooling rate was 0. 2-1 ℃/s， the test steel was mainly composed of softer ferrite structure； When the cooling rate was 3-10 ℃/s， the experimental steel was mainly composed of pearlite struc⁃ ture； When the cooling rate was 20 ℃/s and 30 ℃/s， the structure of the test steel was flat noodles martensite+pearlite； When the cooling rate was 50 ℃/s， a complete martensitic structure was formed at room temperature. The experimental re⁃ sults showed that by reducing the cooling rate to 0. 5-2 ℃/s， ideal ferrite and pearlite hot-rolled structures can be obtained.

Abstract Tumour medical image segmentation plays a crucial role in clinical imaging diagnosis. Existing research has achieved good results, enabling the segmentation of three tumour regions in MRI brain tumour images. Existing models have limited focus on the brain tumour areas, and the long‐term dependency of features is weakened as the network depth increases, resulting in blurred edge segmentation of the targets. Additionally, considering the excellent segmentation performance of the Swin Transformer(Swin‐T) network, its network structure and parameters are relatively large. To address these limitations, this paper proposes a brain tumour segmentation framework with deep nuanced reasoning and Swin‐T. It is mainly composed of the backbone hybrid network (BHN) and the deep micro texture extraction module (DMTE). The BHN combines the Swin‐T stage with a new downsampling transition module called dual path feature reasoning (DPFR). The entire network framework is designed to extract global and local features from multi‐modal data, enabling it to capture and analyze deep texture features in multi‐modal images. It provides significant optimization over the Swin‐T network structure. Experimental results on the BraTS dataset demonstrate that the proposed method outperforms other state‐of‐the‐art models in terms of segmentation performance. The corresponding source codes are available at https://github.com/CurbUni/Brain‐Tumor‐Segmentation‐Framework‐with‐Deep‐Nuanced‐Reasoning‐and‐Swin‐T.

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with "neoantigen-like" NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies.

Abstract Purpose To investigate the value of 2‐deoxy‐18f‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) and circulating tumor cells (CTCs) for the differential diagnosis of patients with benign lung diseases and those with NSCLC. To explore the phenotypic heterogeneity of CTCs and their correlation with FDG uptake in patients with Stage I–IV NSCLC. Methods Blood specimens from patients with benign lung diseases and patients with primary NSCLC were collected for the detection of CTCs and their subtypes (epithelial, mixed, and mesenchymal) and analyzed for 18F‐FDG PET/CT tumor metabolic parameters, including the maximum standardized uptake value (SUVmax), standard uptake value (SUL), metabolic tumor volume of primary lesion (MTV), total lesion glycolysis of primary lesion (TLG). Clinical data including age, gender, smoking history, tumor size, TNM stage and pathology type were also collected. The value of the two method alone and in combination for the differential diagnosis of benign and malignant was comparatively analyzed. Finally, the differences in CTC and its subtypes in different stages of NSCLC were compared, and FDG metabolic parameters were correlated with CTC subtypes. Results There were a total of 65 patients with pulmonary diseases, including 12 patients with benign pulmonary diseases and 53 patients with NSCLC. The mean age was 67 ± 10 (38–89 years), 27 were females and 38 were males. 31 (22 males and 9 females) had a long history of smoking. The mean size of the largest diameter of all single lesions was 36 ± 22 mm with a range of 10–108 mm. Seven out of 12 benign diseases were inflammatory granulomatous lesions and 5 were inflammatory pseudotumours. Twenty‐four out of 53 NSCLC were adenocarcinomas and 29 were squamous carcinomas. Twelve out of 53 patients with NSCLC were in Stage I, 10 were in Stage II, 17 were in Stage III and 14 were in Stage IV. SUVmax, SUL, MTV, TLG, total CTCs, epithelial CTCs, and mixed CTCs were all valuable in the differential diagnosis of benign and malignant. TLG combined with mixed CTCs was statistically different from all other diagnostic methods (p

Endocrine-disrupting chemicals (EDCs) exhibited the detriment in female reproductive health. Our objective was to investigate the individual and mixture effects of EDCs present in follicular fluid, the environment in which oocytes grow and develop, on early reproductive outcomes. We recruited 188 women seeking reproduction examination from the Study of Exposure and Reproductive Health (SEARCH) cohort between December 2020 and November 2021. We assessed the concentrations of 7 categories of 64 EDCs in follicular fluid, and measured early reproductive outcomes, including retrieved oocytes, mature oocytes, normal fertilized oocytes, and high-quality embryos. In this study Monomethyl phthalate (MMP) (2.17 ng/ml) were the compounds found in the highest median concentrations in follicular fluid. After adjusting for multiple testing, multivariate regression showed that multiple EDCs were significantly negatively associated with early assisted reproduction outcomes. For example, MMP showed a significant negative correlation with the number of high quality embryos (β: −0.1, 95 % CI: −0.15, −0.04). Specifically, eight types of EDCs were significantly negatively associated with four early assisted reproductive outcomes (β range: −0.2 ∼ -0.03). In the mixed exposure model, we found that mixtures of EDC were significantly negatively correlated with all four outcomes. In the quantile g-computation (QGCOMP) model, for each interquartile range increase in the concentration of EDC mixtures, the number of oocytes retrieved, mature oocytes, normally fertilized oocytes, and high-quality embryos decreased by 0.46, 0.52, 0.77, and 1.2, respectively. Moreover, we identified that phthalates (PAEs) predominantly contributed to the negative effects. Future research should validate our findings.

As social media influencer endorsement gains significance in marketing communication, an increasing number of influencers have started to incorporate product information into their sponsored content. This study examines the effectiveness of product attribute description in the context of sponsored videos. Using a field dataset of 598 sponsored videos, we demonstrate that influencers' use of product attribute description as an endorsement strategy has a negative impact on video engagement, and this effect is stronger for trial versus awareness campaigns. However, the negative impact is reversed to a positive one when product attribute description is employed for utilitarian products but not for hedonic products. These results reveal that the effectiveness of product attribute description depends on the nature of the product and the campaign objectives. Overall, this study contributes to the understanding of influencer marketing effectiveness and sheds light on the nuances of endorsement strategies. Practical implications on how to optimise endorsement effectiveness and video performance are discussed. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single-variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds [95% confidence interval (CI): 33.6, 1105] of DKD compared with noncarriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% CI: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

5G Multicast Broadcast Services (MBS) are viewed as a promising 5G New Radio (NR) application, as standardization begins in 3GPP Release 17. With MBS, one next generation Node B (gNB) delivers data to multiple user equipments (UE) simultaneously, thus improving spectrum efficiency. Millimeter wave (mmWave) beamforming further enhances system performance by focusing signals in a dedicated direction. However, despite the advantages, we identify three issues of multicast with beamforming techniques. First, link directionality causes the gNB to transmit data over the beams sequentially, resulting in a combinatorial resource allocation problem. Confronting this beam scheduling issue, we develop an optimization algorithm that obtains an optimal solution in polynomial time. Second, UEs may falsely report their valuations over beam resources to gain more utility. Under this scenario, the gNB cannot allocate the resources to those in need due to the lack of accurate UE information. Therefore, we propose a Vickrey-Clarke-Groves (VCG) auction-based mechanism to incentivize the UEs to reveal their valuations over resources truthfully. This mechanism guarantees solution efficiency and maximizes social welfare. Third, as 3GPP standards allow for different priorities for different multicast flows, and video content providers distinguish between ordinary and premium UEs, we take UE priority into account. In this regard, we extend the valuation-based mechanism to a multi-priority one. Finally, the mathematical analysis validates some desirable properties of the proposed scheme, such as incentive-compatibility. Simulation results also justify our superior performance in the 5G MBS system compared with other resource allocation schemes.

Abstract Background Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. Methods In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. Results First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. Conclusions Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.

Under the background of “dual-carbon” goal and current technological conditions, coal, waste and carbon constitute an impossible triangle in the coal industry which severely constrains its green, low-carbon, and sustainable development. Adhering to the principles of treating waste with waste and returning the waste to where it comes from, with a focus on the three-dimensional perspectives of damage reduction in coal mining, the functional utilization of mining waste, and low-carbon disposal of carbon in mining industry, this paper explores a synergistic development path for coal, waste and carbon. It provides a comprehensive solution to unravel the impossible triangle and promote the overall green, low-carbon development of coal industry. The specific contributions of this work include: ① Clarifying the scientific connotation of damage reduction in coal mining, the spatial combination characteristics of aquifers in the ecologically fragile areas, the movement patterns of overlying strata under the application of coal mining damage reduction techniques, and the surface deformation patterns resulting from overlying strata damage; proposing the original technologies of drilling-backfilling-retention for section pillar extraction, narrow strip mining with backfill, and backfilling behind fully-mechanized longwall face aiming to address the challenges posed by damage reduction mining; ② Interpreting the scientific connotation of functional utilization for mining waste; clarifying the scientific issues related to the modification methods and mechanisms of magnesium-coal-based solid waste material, the mechanisms of synergistic interactions among diverse solid wastes, and the properties control of total solid waste backfilling materials. These efforts have led to the establishment of a key technological system for the functional utilization of solid waste, with a core focus on the modification of solid waste raw materials, the development of solid waste-based cementitious materials, and the preparation of solid waste based backfilling materials; ③ Elucidating the scientific connotation of low-carbon disposal of carbon with a scientific practical framework and implementation pathway; clarifying some scientific issues related to mineralization material preparation, storage space construction, CO2 storage and control mechanisms, the long-term environmental effects of CO2 storage, and reservoir stability in the low-carbon disposal process of carbon. The scientific issues related to mineralization material preparation, seal space key technologies such as fractured space CO2 storage and CO2 sequestration through coal mine carbon solidification are explicitly defined which results in a new model for achieving a low-carbon CO2 storage in coal mine goaf. Based on the green, low-carbon and sustainable development of coal industry, it is of great significance to collaboratively promote the damage reduction in coal mining, the functional utilization of mining waste, and the low-carbon disposal of carbon. This coordinated effort plays a crucial role in advancing the realization of the dual-carbon goal in the coal industry.

Abstract Background Previous studies of singletons evaluating prenatal phthalate exposure and early neurodevelopment reported mixed results and the associations could be biased by parental, obstetrical, and genetic factors. Methods A co-twin control design was employed to test whether prenatal phthalate exposure was associated with children’s neurocognitive development. We collected information from 97 mother-twin pairs enrolled in the Wuhan Twin Birth Cohort between March 2016 and October 2018. Fourteen phthalate metabolites were measured in maternal urine collected at each trimester. Neurodevelopmental differences in twins at the age of two were examined as the outcome of interest. Multiple informant model was used to examine the covariate-adjusted associations of prenatal phthalate exposure with mental development index (MDI) and psychomotor development index (PDI) scores assessed at 2 years of age based on Bayley Scales of Infant Development (Second Edition). This model also helps to identify the exposure window of susceptibility. Results Maternal urinary levels of mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (β = 1.91, 95% CI: 0.43, 3.39), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (β = 1.56, 95% CI: 0.33, 2.79), and the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) (β = 1.85, 95% CI: 0.39, 3.31) during the first trimester showed the strongest and significant positive associations with intra-twin MDI difference. When stratified with twin chorionicity, the positive associations of monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), individual DEHP metabolites, and ∑DEHP exposure during pregnancy with intra-twin neurodevelopmental differences were more significant in monochorionic diamniotic (MCDA) twins than those in dichorionic diamniotic (DCDA) twins. Conclusions Neurodevelopmental differences in MCDA twins were strongly associated with prenatal phthalate exposure. Our findings warrant further confirmation in longitudinal studies with larger sample sizes.