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Abstract Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

In the context of high-quality urban renewal, we recognize that heritage renewal must align with sustainable conservation. As an important part of cultural heritage, we find that the conservation value of industrial heritage is often undermined in the pre-decision-making and mid-development phases of adaptive reuse, resulting in an imbalance between sustainable conservation and renewal. The study aims to develop a comprehensive, concise, and objective post-development assessment system for the adaptive reuse of industrial heritage. We establish an assessment system based on the “conservation sustainability” and “added value sustainability” of industrial heritage and create a two-dimensional “conservation–reuse” assessment model. Using the geographic information system (GIS), we build a database of Beijing industrial heritage and assess 19 reused samples with the four-quadrant model. The results show that “added value sustainability” fluctuates between 53.3% and 86.7%, while “conservation sustainability” reaches a low of only 50%, with more than half of the heritage having a conservation degree below the average. This highlights the need for stronger conservation efforts. The findings and methodology of this study provide a database and guidelines for decision-makers to adjust reuse models in a timely manner, ensuring sustainable conservation. Compared to previous assessment models, this model is easier to operate and allows decision-makers to control the dynamic balance of “conservation–reuse” in sustainable renewal.

Amorphous magnesium (Mg) alloy, especially Mg–Zn–Ca series, has been receiving continuous attention in biomedical field, because of its favorable corrosion resistance, suitable modulus and biocompatibility. In this work, laser powder bed fusing (LPBF) with unique characteristics of rapid solidification and layer-by-layer fashion was used to fabricate bulk Mg–Zn–Ca and Mg–Zn–Ca–Y amorphous parts. It was revealed that the as-built parts contained amorphous structure, since the molten pool experienced an extremely high cooling rate that suppressed ordered arrangement of atoms. A few of nanocrystals (α-Mg and Ca2Mg5Zn13) were obtained due to repeated heat accumulation in heat-affected zones. More significantly, Y alloying altered the glass forming ability and stimulated in-situ formation of quasicrystal I-phase with high hardness and elastic modulus, which not only acted as reinforced particles, but also retarded the propagation of shear bond and thereby excited the emergence of secondary shear bands and vein patterns. Thus, Mg–Zn–Ca–Y part exhibited simultaneously improved yield strength and plasticity. Despite the micro galvanic corrosion induced by crystalline phases, it exhibited a moderate corrosion rate. Furthermore, in vitro cell tests proved its favorable biocompatibility. Our work highlighted the feasibility to prepare amorphous Mg alloy with controllable performance.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) associated with cognitive impairment (CI) is acknowledged. However, the underlying pathogenesis and involvement of the immune system remain unclear. Objectives This study aimed to investigate the alterations in immune cells, cytokines, and GABA+ levels in NMOSD patients with cognitive deficits. Methods Thirty‐eight NMOSD patients and 38 healthy controls (HCs) were included. NMOSD patients were stratified as NMOSD‐CI and NMOSD‐CP groups. The difference in cognitive functions, Tfh and cytokines, and GABA+ levels were assessed, and their correlations were calculated. Results NMOSD‐CI patients showed worse performance on all cognitive tests, and the percentage of circulating follicular helper T cells (cTfh) was significantly elevated. The frequency of cTfh was positively and negatively correlated with Stroop‐A and AVLT long‐delayed scores, respectively. IL‐21 was remarkably higher in NMOSD‐CI and NMOSD‐CP. The level of GABA+ in medial prefrontal cortex (mPFC) was significantly decreased in NMOSD‐CI and was proved positively and negatively correlated with Symbol Digit Modalities Test and the frequency of circulating Tfh cells, respectively. Conclusion In NMOSD‐CI patients, all cognitive domains were impacted, , while GABA+ levels in mPFC were decreased. GABA+ levels in NMOSD‐CI were negatively correlated with the frequency of cTfh, suggesting the underlying coupling mechanism between immune responses and neurotransmitter metabolism in CI in NMOSD patients.

Abstract Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.

Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune, astrocytopathic diseases affecting the central nervous system(CNS), especially the central optic nerve and spinal cord. Aquaporin 4-immunoglobulin G (AQP4-IgG) is the dominant pathogenic antibody and can be detected in about 80% of patients with NMOSD. Although only a few cases were reported on NMOSD associated with cancer, they demonstrated the potential paraneoplastic link between cancer and NMOSD. In the present study, we report three NMOSD cases associated with cancer, which are teratoma and lung adenocarcinoma, teratoma, and transverse colon adenocarcinoma, respectively. Pathological staining of tumor sections revealed a high AQP4 expression. After tumor removal, all cases were stable and suffered no further relapses, which revealed the potential paraneoplastic mechanism between cancer and NMOSD. One of our patient's serum AQP4-IgG was transiently slightly elevated even though AQP4 was highly expressed in tumor cells, which indicates that AQP4 is not the main pathogenic antibody but might be induced by other underlying pathogenic antibody–antigen reactions.

Abstract Background Interactions of microbes and diseases are of great importance for biomedical research. However, large-scale of microbe–disease interactions are hidden in the biomedical literature. The structured databases for microbe–disease interactions are in limited amounts. In this paper, we aim to construct a large-scale database for microbe–disease interactions automatically. We attained this goal via applying text mining methods based on a deep learning model with a moderate curation cost. We also built a user-friendly web interface that allows researchers to navigate and query required information. Results Firstly, we manually constructed a golden-standard corpus and a sliver-standard corpus (SSC) for microbe–disease interactions for curation. Moreover, we proposed a text mining framework for microbe–disease interaction extraction based on a pretrained model BERE. We applied named entity recognition tools to detect microbe and disease mentions from the free biomedical texts. After that, we fine-tuned the pretrained model BERE to recognize relations between targeted entities, which was originally built for drug–target interactions or drug–drug interactions. The introduction of SSC for model fine-tuning greatly improved detection performance for microbe–disease interactions, with an average reduction in error of approximately 10%. The MDIDB website offers data browsing, custom searching for specific diseases or microbes, and batch downloading. Conclusions Evaluation results demonstrate that our method outperform the baseline model (rule-based PKDE4J) with an average $$F_1$$ F 1 -score of 73.81%. For further validation, we randomly sampled nearly 1000 predicted interactions by our model, and manually checked the correctness of each interaction, which gives a 73% accuracy. The MDIDB webiste is freely avaliable throuth http://dbmdi.com/index/

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the therapeutic landscape of haematological malignancies. However, resistance and relapse remain prominent limitations, and they are related to the limited persistence and efficacy of CAR T cells, downregulation or loss of tumour antigens, intrinsic resistance of tumours to death signalling, and immune suppressive microenvironment. Rational combined modality treatments are regarded as a promising strategy to further unlock the antitumor potential of CAR T cell therapy, which can be applied before CAR T cell infusion as a conditioning regimen or in ex vivo culture settings as well as concomitant with or after CAR T cell infusion. In this review, we summarize the combinatorial strategies, including chemotherapy, radiotherapy, haematopoietic stem cell transplantation, targeted therapies and other immunotherapies, in an effort to further enhance the effectiveness of this impressive therapy and benefit more patients.

With high permeability and low modulus, the cellular substrate can achieve larger elastic stretchability and better wearing comfort than the solid substrate used for stretchable electronics. Since the porosity of the cellular substrate is a dimensionless ratio value, a fixed porosity can result in innumerable cell sizes. And different cell sizes will bring different stiffness, which has a strong impact on the elastic stretchability of stretchable electronics. In this paper, a numerical model is established for a particular structure where the serpentine interconnect is bonded on cellular substrates with the fixed porosity (ϕ=80%). Eight different cell sizes are selected for this porosity and two stretching directions, along and normal to the cell walls, are studied. Base on the results from the model, the curves of elastic stretchability versus the ratio of wall width to serpentine width ratio (δ/w) can be obtained. Results demonstrate that the appropriate ratio δ/w≈1 yields significantly larger elastic stretchability than other cell sizes of cellular substrates. This finding can provide an engineering design regulation for stretchable electronics based on cellular substrates.

BackgroundThis study aimed to systematically evaluate and compare the efficacy and safety of consolidative hematopoietic stem cell transplantation (HSCT) after CD19 chimeric antigen receptor T (CAR-T) therapy with non-HSCT in the treatment of acute lymphoblastic leukemia (ALL).MethodsThe PubMed, Embase, Cochrane Library and Web of Science databases were searched for clinical trials. Pooled hazard ratios (HRs) for overall survival (OS), relapse rate, and leukemia-free survival (LFS) as well as overall incidence rates for transplant-related mortality (TRM), acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and infections were calculated using Stata software.ResultsWe screened 3,441 studies and identified 19 eligible studies with 690 patients. Among the patients who achieved complete remission (CR) after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (HR = 0.34, 95% CI, 0.17–0.68, P = 0.003), the relapse rate (HR = 0.16, 95% CI, 0.10–0.25, P < 0.001), and LFS (HR = 0.15, 95% CI, 0.08–0.28, P < 0.001). For patients who achieved MRD-negative (neg) CR after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (0.57, 95% CI, 0.33–0.99, P = 0.045), the relapse rate (0.14, 95% CI, 0.06–0.31, P < 0.001), and LFS (0.21, 95% CI, 0.12–0.35, P < 0.001). Regarding safety, we calculated pooled incidence rates for TRM (8%, 95% CI, 0.02–0.15), aGVHD (44%, 95% CI, 0.23–0.67), cGVHD (36%, 95% CI, 0.17–0.56), and infections (39%, 95% CI, 0.03–0.83).ConclusionsCompared with non-HSCT treatment, consolidative HSCT after CD19 CAR-T therapy for R/R B-ALL patients can prolong OS and LFS and reduce the risk of relapse. The incidence rates for adverse events are acceptable. More high-quality randomized controlled trials are required to avoid bias and further determine the efficacy of HSCT.

Chimeric antigen receptor (CAR) T-cell therapy exhibits desirable and robust efficacy in patients with acute lymphoblastic leukemia (ALL). Stimulated by the revolutionized progress in the use of FDA-approved CD19 CAR T cells, novel agents with CAR designs and targets are being produced in pursuit of superior performance. However, on the path from bench to bedside, new challenges emerge. Accessibility is considered the initial barrier to the transformation of this patient-specific product into a commercially available product. To ensure infusion safety, profound comprehension of adverse events and proactive intervention are required. Additionally, resistance and relapse are the most critical and intractable issues in CAR T-cell therapy for ALL, thus precluding its further development. Understanding the limitations through up-to-date insights and characterizing multiple strategies will be critical to leverage CAR T-cell therapy flexibly for use in clinical situations. Herein, we provide an overview of the application of CAR T-cell therapy in ALL, emphasizing the main challenges and potential clinical strategies in an effort to promote a standardized set of treatment paradigms for ALL.

Interleukin-1 receptor antagonist is an important acute-phase protein and an immune mediator, and its expression is associated with the development of hepatitis or acute liver failure. The aim of this study was to investigate whether recombinant human interleukin-1 receptor antagonist directly targets and improves cell survival in a carbon tetrachloride-induced hepatocyte injury model in vitro. A human hepatoma cell line and a mouse hepatocyte cell line were used to establish carbon tetrachloride-induced cell injury models in vitro, and cell viability, apoptosis, and reactive oxygen species level were determined to assess the degree of hepatocellular damage. Quantitative real-time polymerase chain reaction was used to analyze the level of interleukin-1β, interleukin-6, and tumor necrosis factor-α mRNA in cells; extracellular regulated protein kinases 1/2 phosphorylation in hepatocytes was analyzed using western blotting. Recombinant human interleukin-1 receptor antagonist could directly target hepatocytes, improve cell survival, and decrease carbon tetrachloride-induced cell apoptosis in vitro. In hepatocytes, recombinant human interleukin-1 receptor antagonist remarkably downregulated expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α in hepatocytes exposed to carbon tetrachloride. It also decreased accumulation of reactive oxygen species and abrogated the suppression of extracellular regulated protein kinases 1/2 phosphorylation induced by carbon tetrachloride. However, stimulation of cells with an extracellular regulated protein kinases 1/2 inhibitor blocked the recombinant human interleukin-1 receptor antagonist-induced upregulation of extracellular regulated protein kinase1/2 activation and abrogated the improvement in hepatocyte survival following carbon tetrachloride treatment. Collectively, these findings provide new insights into the hepatocyte-protective mechanism of recombinant human interleukin-1 receptor antagonist.

Wire arc additive manufacturing (WAAM) is capable of rapidly depositing metal materials thus facilitating the fabrication of large-shape metal components. However, due to the multi-process-variability in the WAAM process, the deposited shape (bead width, height, depth of penetration) is difficult to predict and control within the desired level. Ultimately, the overall build will not achieve a near-net shape and will further hinder the part from performing its functionality without post-processing. Previous research primarily utilizes data analytical models (e.g., regression model, artificial neural network (ANN)) to forwardly predict the deposition width and height variation based on single or cross-linked process variables. However, these methods cannot effectively determine the optimal printable zone based on the desired deposition shape due to the inability to inversely deduce from these data analytical models. Additionally, the process variables are intercorrelated, and the bead width, height, and depth of penetration are highly codependent. Therefore, existing analysis cannot grant a reliable prediction model that allows the deposition (bead width, height, and penetration height) to remain within the desired level. This paper presents a novel machine learning framework for quantitatively analyzing the correlated relationship between the process parameters and deposition shape, thus providing an optimal process parameter selection to control the final deposition geometry. The proposed machine learning framework can systematically and quantitatively predict the deposition shape rather than just qualitatively as with other existing machine learning methods. The prediction model can also present the complex process-quality relations, and the determination of the deposition quality can guide the WAAM to be more prognostic and reliable. The correctness and effectiveness of the proposed quantitative process-quality analysis will be validated through experiments.

The selective laser melting (SLM) process provides a more extensive design space and manufacturability. However, it is still hindered by its inaccuracy in dimension and functionality. The distortion in the SLM process affects the dimensional accuracy of the component and may even hinder the SLM process. Still, the distortion mechanism has not been well explained; specifically, the effects from the process parameters and scan strategies on the distortion have not been sufficiently investigated. In this study, a quantitative model that considers displacements, plastic strains, and thermal strains on each layer is developed to analyze the distortion mechanism. The distortion is found to be induced by a residual stress gradient among the layers. Then, a transient numerical method calculates residual stress, plastic strain, and distortion in the SLM process. Different simulations with various layers, scanning speeds, stiffness of support structures, and scan strategies are performed to study the relationship between process parameters and distortion. It can be found that the distortion decreases as the height increases. The distortion increases with the scanning speed, reaching the maximum at 700 mm/s and then dropping. We concluded that increasing the stiffness of the support structures is beneficial to reduce the distortion and changing the scanning direction among layers is useless to reduce the distortion. This study gives a theoretical model to analyze the distortion and provides guidance for reducing distortions in the SLM process.

As an important part of the navigation facilities for water conservancy and electricity in Gezhouba, the operation safety of herringbone gates is critical. Due to the minor torsional stiffness of the gate, it is easy to produce torsional deformation during operating under the water pressure, wind load, and gravity, which may lead to fatigue damage. In this study, a gate model with a combination of plate unit and the solid unit was developed, taking a ship lock herringbone gate as an example. According to the gate load under different working conditions, such as self-weight, surge, etc., in this research, we used the finite element analysis software ANSYS to analyze and calculate the stress and strain of the gate, with and without a back tie, and obtained the characteristics of the gate torsional deformation under various working conditions. The results show that the gate’s deformation degree and the direction under different working conditions vary greatly. The maximum deformation point mostly appears in the upper or lower corners of the oblique joint column. The gate deformation can be significantly reduced by adding the back tie. The research results provide a theoretical basis for further optimizing the design of the gate and installation of the back tie to reduce the fatigue damage of the miter gate.

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics.

Aim NIH3T3 cell line with expression of human receptor for advanced glycation end-products (hRAGE) transduced with lentivirus vectors was used to analyze affinity, biological activity, and/or molecular mechanisms of molecules targeting the hRAGE pathway. Method The DNA fragment coding for hRAGE gene was integrated into the genome of NIH3T3 cells using lentivirus transduction. Cells expressing hRAGE were selected with puromycin, and the level of hRAGE expression was analyzed by Western blot. To establish a stable cell line, colonies of hRAGE-expressing cells were generated, and the level of RAGE expression in each engineered cell line was analyzed within 20 generations. Flow cytometry assay was used to verify affinity of anti-hRAGE antibody binding to hRAGE on the surface of engineered cells. The engineered NIH3T3 cell line was applied to assess effects of anti-hRAGE blocking antibody on amyloid β-induced cells apoptosis by CCK-8 assay. Results The engineered NIH3T3 cell line (hRAGE-NIH3T3) could stably express human RAGE. Commercial anti-RAGE polyclonal antibody could recognize and bind to human RAGE on the surface of hRAGE-NIH3T3 but not original NIH3T3 cells. In addition, hRAGE-NIH3T3 was more sensitive to RAGE pathway-dependent stimulation. Our data show that the hRAGE-NIH3T3 cell line established is an excellent tool in the study of RAGE-targeting molecules based on the cellular level, biological function, and RAGE-mediated molecular mechanisms.

The fused filament fabrication (FFF) process deposits thermoplastic material in a layer-by-layer manner, expanding the design space and manufacturing capability compared with traditional manufacturing. However, the FFF process is inherently directional as the material is deposited in a layer-wise manner. Therefore, the in-plane material cannot reach the isotropy character when performing the tensile test. This would cause the strength of the print components to vary based on the different process planning selections (building orientation, toolpath pattern). The existing toolpaths, primarily used in the FFF process, are linear, zigzag, and contour toolpaths, which always accumulate long filaments and are unidirectional. Thus, this would create difficulties in improving the mechanical strength from the existing toolpath strategies due to the material in-plane anisotropy. In this paper, an in-plane isotropy toolpath pattern is generated to enhance the mechanical strength in the FFF process. The in-plane isotropy can be achieved through continuous deposition while maintaining randomized distribution within a layer. By analyzing the tensile strength on the specimens made by traditional in-plane anisotropy toolpath and the proposed in-plane isotropy toolpath, our results suggest that the mechanical strength can be reinforced by at least 20% using our proposed toolpath strategy in extrusion-based additive manufacturing.