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Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by ASCL1 , NEUROD1 , HNF4A , POU2F3 , and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered HNF4A -dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1 , unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities. [Display omitted] • Pan-cancer alignment reveals convergence of NECs arising from different tissues • Divergence in transcriptional programs defines five cross-tissue intrinsic subtypes • HNF4A-driven NEC subtype shows distinct molecular and clinicopathological traits • Context-dependent subtype prevalence underlies inter- and intra-tissue heterogeneity Neuroendocrine carcinoma (NEC) is a rare and highly heterogeneous class of malignancies that can occur in various organs throughout the body. In this study, Wang et al. propose a uniform classification framework that classifies NEC into five cross-tissue intrinsic subtypes exhibiting distinct transcriptional programs and identify a unique subtype driven by gastrointestinal lineage transcription factors (TFs). [ABSTRACT FROM AUTHOR]

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth in vivo. Thus, the necessary impact of integral lysosomal function in cell rescue and death were illustrated. LW-218-induced cholesterol accumulation on lysosomes via NPC1 binding can elicit lysosomal damage followed by lysophagy and lysosome-dependent cell death in hematological malignancies cells. [Display omitted] [ABSTRACT FROM AUTHOR]

This paper presents a method to allow the measurement of residual stress ( σ r ), yield strength ( σ y ) and strain hardening exponent (n) of metal materials through continuous spherical indentation test. Based on the analysis of finite element simulation results, a new fitting equation between the indentation response parameter and the material properties was given in this paper. The influence of friction and the mesh size of finite element model was also discussed when the residual stress is included in the material. Only three load values are required at each different indentation depths, and the three unknown parameters ( σ r , σ y and n) can be obtained through corresponding dimensionless functions based on the reverse analysis. Finally, the validation of the method presented in this paper was verified by simulating the material (SUS304) with the known material parameters in the literature. Results show that the method proposed in this paper can accurately predict the residual stress, yield strength and strain hardening exponent of metal materials from the indentation load-depth curve. • In this paper, a new dimensionless function l n P / (σ y ⋅ h 2) = ∏ * (E / σ y , n , σ r / σ y) is given for material parameters and residual stresses. • The effect of friction and size of element mesh on the model is negligible for a material with residual stress. • A reverse analysis algorithm can be used to estimate the residual stress of metal material without plastic plateau. [ABSTRACT FROM AUTHOR]

• Based on the idea of reverse modeling, a finite element modeling method for CT images is proposed. • NURBS is utilized to fit complex boundary of model, which can greatly improve the finite element computational efficiency while ensuring the accuracy of the model. • The mechanical properties and failure modes of interlocked structures were studied by experiments and simulations. • The failure mode of structure is related to arrangement of pores, which can be improved by adjusting the printing strategy. Suture-inspired interlocked interfaces in nature exhibit promising industrial application potentials for advanced mechanical structures, devices and equipment. It is of significant scientific interest for studying the pull-out response and failure mode of interlocked structure as well as internal stress variations during the loading process. In this paper, finite element analysis (FEA) simulation based on X-Ray tomographic images is proposed for understanding the effects of manufacturing defects on the performances of interlocked structures, which are of critical importance for controlling the stress evolution of the interface structure and corresponding failure modes. Firstly, X-ray micro computed tomography (micro-CT) was applied for non-destructive scanning inspection of aluminum alloy additive manufacturing samples, high spatial resolution and calculation efficiency can be realized through tomographic image guided FEA scheme for generating high fidelity simulation results. Afterwards, non-uniform rational B-splines fitting method was employed for optimizing sample boundaries harvested from CT images, which allows smooth conversion from CT pixel images to high precision fitted finite element model. The B-spine fitting model can significantly improve the computational efficiency for finite element simulation without losing calculation reliability and resolution, overcoming the inherent contradictions between efficiency and resolution of the traditional pixel image finite element method. Finally, considering the mechanical contributions and interactions of external and internal porosity defects, the failure modes of the interlocked structures were further analyzed based on the results of finite element analysis. [ABSTRACT FROM AUTHOR]

The structural, mechanical, electronic, and optical properties of B 6 O were explored by means of first-principles calculations. Such a system is mechanically stable and also a relatively hard material which are derived from obtained elastic constants and bulk moduli. Bulk B 6 O is a direct-gap semiconductor with a bandgap of about 2.93 eV within G 0 W 0 approximation. Furthermore, the optical properties, such as real and imaginary parts of dielectric functions, refractive index and extinction coefficient, and the comparison of optical properties between the density-functional theory (DFT) and G 0 W 0 Bethe–Salpeter equation (G 0 W 0 -BSE) results, were computed and discussed. The results obtained from our calculations open a possibility for expanding its use in device applications. [ABSTRACT FROM AUTHOR]

The vibrational properties, electronic structures and optical properties of novel carbon allotropes, such as monolayer penta-graphene (PG), double-layer PG and T12-carbon, were studied by first-principles calculations. Results of phonon calculations demonstrate that these exotic carbon allotropes are dynamically stable. The bulk T12 phase is an indirect-gap semiconductor having a quasiparticle (QP) bandgap of ∼5.19 eV. When the bulk material transforms to a two-dimensional (2D) phase, the monolayer and double-layer PG become quasi-direct gap semiconductors with smaller QP bandgaps of ∼4.48 eV and ∼3.67 eV, respectively. Furthermore, the partial charge density analysis indicates that the 2D phases retain part of the electronic characteristics of the T12 phase. The linear photon energy-dependent dielectric functions and related optical properties including refractive index, extinction coefficient, absorption spectrum, reflectivity, and energy-loss spectrum were also computed and discussed. Additionally, the chemical stability of monolayer PG and the electronic and optical properties of double-side hydrogenated monolayer PG were also investigated. The results obtained from our calculations are beneficial to practical applications of these exotic carbon allotropes in optoelectronics and electronics. [ABSTRACT FROM AUTHOR]

• Deep-learning based models help physician make radiotherapy planning. • Most dose prediction methods only use binary masks as inputs without distance information. • An explicit distance transformation is performed before the network. • This work demonstrated the effectiveness and generalizability of our distance transformation. Geometric information such as distance information is essential for dose calculations in radiotherapy. However, state-of-the-art dose prediction methods use only binary masks without distance information. This study aims to develop a dose prediction deep learning method for nasopharyngeal carcinoma radiotherapy by taking advantage of the distance information as well as the mask information. A novel transformation method based on boundary distance was proposed to facilitate the prediction of dose distributions. Radiotherapy datasets of 161 nasopharyngeal carcinoma patients were retrospectively collected, including binary masks of organs-at-risk (OARs) and targets, planning CT, and clinical plans. The patients were randomly divided into 130, 11 and 20 cases for training, validating, and testing the models, respectively. Furthermore, 40 patients from an external cohort were used to test the generalizability of the models. The proposed method shows superior performance. The predicted dose error and dose–volume histogram (DVH) error of our method were 7.51% and 11.6% lower than the mask-based method, respectively. For the inverse planning, compared with mask-based methods, our method provided similar performances on the GTVnx and OARs and outperformed on the GTVnd and the CTV, the pass rates of which increased from 89.490% and 90.016% to 96.694% and 91.189%, respectively. The preliminary results on nasopharyngeal carcinoma radiotherapy cases showed that our proposed distance-guided method for dose prediction achieved better performance than mask-based methods. Further studies with more patients and on other cancer sites are warranted to fully validate the proposed method. [ABSTRACT FROM AUTHOR]

Suture-inspired interlocked interfaces in nature exhibit promising industrial applications potentials in advanced mechanical structures, devices and equipment. In this paper, the parametric design of interlocked interfaces is performed, and selective laser melting (SLM) additive manufacturing tensile specimens and compact tension (CT) fracture specimens with sutured interfaces are harvested, where AlSi 10 Mg raw materials are used as constituent materials. Afterwards, compact tension tensile fracture experiments and corresponding finite element simulations were performed and compared, where force-displacement curves for different interface structural geometrical parameters were harvested. The mechanical properties and failure modes of the interlocked interface structures were analyzed through experiments and simulations verification. Crack-tip opening displacement (CTOD) and fracture energy criteria were used to evaluate the fracture toughness of the interlocked specimen interfaces. In addition, parametric analysis was carried out to investigate the influence of different interlocked structural parameters on the interface mechanical performances and failure features. Accordingly, it can be concluded that the interface strength, toughness, and failure mechanisms can be rationally tuned through given geometrical parameters of the re-entrant interface microstructures. [ABSTRACT FROM AUTHOR]

T-cell malignancies are characterized by the excessive proliferation of hematopoietic precursor cells of T-cell lineage lymphocytes in the bone marrow. Previous studies suggest that T-cell malignancies are usually accompanied by highly activated PI3K/AKT signaling which confers the ability of cancer cells to proliferate and survive. Here, we found that GL-V9, a newly synthesized flavonoid compound, had a potent to inhibit the activation of AKT1 and induce the cell apoptosis in T-cell malignancies including cell lines and primary lymphoblastic leukemia. Results showed that GL-V9-induced degradation of AKT1 blocked PI3K/AKT1 signaling and the degradation of AKT1 could be reversed by NH 4 Cl, an inhibitor of lysosomal function. Inhibiting AKT1 promoted dephosphorylation of FOXO3A and its nuclear translocation. We further demonstrated that GL-V9-induced apoptosis effects were dependent on the binding of FOXO3A to the BIM promoter, resulting in the production of BH3-only protein BIM. Moreover, GL-V9 showed a more persistent and stronger apoptosis induction effects than pharmacologic PI3K inhibitor. The in vivo studies also verified that GL-V9 possessed the anti-tumor effects by reducing the leukemic burden in T-ALL-bearing BALB/c nude mice. In conclusion, our study provides a new insight into the mechanism of GL-V9-induced apoptosis, suggesting the potency of GL-V9 to be a promising agent against T-cell malignancies. Image 1 • GL-V9-induced degradation of AKT blocked PI3K/AKT signaling and the degradation of AKT could be reversed by NH 4 Cl. • GL-V9 induces apoptosis through AKT/FOXO3A/BIM axis. • GL-V9 shows more rapid and persistent effects on AKT inhibition and apoptosis induction than PI3K inhibitor. [ABSTRACT FROM AUTHOR]