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Hepatocellular carcinoma (HCC) is a major leading cause of cancer-related death worldwide. Alpha fetoprotein (AFP) is reactivated in a majority of hepatocellular carcinoma (HCC) and associated with poor patient outcomes. Although increasing evidence has shown that AFP can regulate HCC cell growth, the precise functions of AFP in hepatocarcinogenesis and the associated underlying mechanism remain incompletely understood. In this study, we demostrated that depleting AFP significantly suppressed diethylnitrosamine (DEN)-induced liver tumor progression in an AFP gene-deficient mouse model. Similarly, knocking down AFP expression inhibited human HCC cell proliferation and tumor growth by inducing apoptosis. AFP expression level was inversely associated with the apoptotic rate in mouse and human HCC specimens. Investigation of potential cross-talk between AFP and apoptotic signaling revealed that AFP exerted its growth-promoting effect by suppressing the Fas/FADD-mediated extrinsic apoptotic pathway. Mechanistically, AFP bound to the RNA-binding protein HuR, increasing the accumulation of HuR in the cytoplasm and subsequent inhibition of Fas mRNA translation. In addition, we found that inhibiting AFP enhanced the cytotoxicity of therapeutics to AFP-positive HCC cells by activating HuR-mediated Fas/FADD apoptotic signaling. Conclusion: Our study defined the pro-oncogenic role of AFP in HCC progression and uncovered a novel antiapoptotic mechanism connecting AFP to HuR-mediated Fas translation. Our findings suggest that AFP is involved in the pathogenesis and chemosensitivity of HCC and that blockade of AFP may be a promising strategy to treat advanced HCC.

Gastric neuroendocrine carcinoma (GNEC), a heterogeneous group of neuroendocrine neoplasms (NENs) derived from gastric neuroendocrine cells, has been shown to be more aggressive and chemoresistant in gastric cancer, which contributes to the poor prognosis. We analysed transcriptome profiles of tumor/non-tumor tissue from GNEC patients and GNEC cell lines to explore the underlying mechanisms. Our results suggest a critical role for synaptosomal-associated protein 25 kDa (SNAP25) in GNEC. SNAP25 was found to stabilize Akt via modulating its monoubiquitination. We further identified RUN domain containing 3A (RUNDC3A) as an upstream molecule that regulates SNAP25 expression, which is associated with tumor progression and chemoresistance in GNECs. Moreover, these findings were extended into multiple NENs including neuroendocrine carcinomas in the intestinal tract, lungs and pancreas. Identifying the RUNDC3A/SNAP25/Akt axis in NENs may provide a novel insight into the potential therapeutic target for patients with NENs.

The hydrostatic guideway has been widely used in ultra-precision machine tools. The flow stability of the hydrostatic guideway has a significant impact on its bearing characteristics, and the flow controller is critical to safeguard the flow stability of the hydrostatic guideway. Currently, most engineering applications use fixed, fluid-resistance flow controllers, which have a simple structure, low cost, and high reliability. However, when facing complex working conditions, the fixed, fluid-resistance flow controller cannot maintain the flow stability of the hydrostatic guide. In this study, a membrane-type flow controller with variable fluid resistance is designed, and a theoretical model of the flow controller’s bearing characteristics is established, which is verified by fluid–solid coupling simulation and flow rate experiments. Analyzing the influence of the design parameters of the membrane-type flow controller on the performance according to the theoretical model, the design guidelines of the membrane-type flow controller are established, the key structure of the flow controller is clarified, and the design range of the key structure dimensions is given. The results show that the gasket thickness of the membrane-type flow controller has the greatest impact on the performance of the hydrostatic guideways, which should be ensured to have a machining error of less than 0.005 mm. This study is a guide for the design and manufacture of flow controllers, as well as for engineering applications.

Background/AimsHematocrit is a widely used biomarker to guide early fluid therapy for patients with acute pancreatitis (AP), but there is controversy over whether early rapid fluid therapy (ERFT) should be used in hemoconcentrated patients. This study investigated the association of hematocrit and ERFT with clinical outcomes of patients with AP.MethodsData from prospectively maintained AP database and retrospectively collected fluid management details were stratified according to actual severity defined by revised Atlanta classification. Hemoconcentration and “early” were defined as hematocrit > 44% and the first 6 h of general ward admission, respectively, and “rapid” fluid rate was defined as ≥ 3 ml/kg/h. Patients were allocated into 4 groups for comparisons: group A, hematocrit ≤ 44% and fluid rate < 3 ml/kg/h; group B, hematocrit ≤ 44% and fluid rate ≥ 3 ml/kg/h; group C, hematocrit > 44% and fluid rate < 3 ml/kg/h; and group D, hematocrit > 44% and fluid rate ≥ 3 ml/kg/h. Primary outcome was rate of noninvasive positive-pressure ventilation (NPPV).ResultsA total of 912 consecutive AP patients were analyzed. ERFT has no impact on clinical outcomes of hemoconcentrated, non-severe or all non-hemoconcentrated AP patients. In hemoconcentrated patients with severe AP (SAP), ERFT was accompanied with increased risk of NPPV (odds ratio 5.96, 95% CI 1.57–22.6). Multivariate regression analyses confirmed ERFT and hemoconcentration were significantly and independently associated with persistent organ failure and mortality in patients with SAP.ConclusionsERFT is associated with increased rate of NPPV in hemoconcentrated patients with SAP.

Lateral momentum conservation is typically kept in a non-absorptive rotationally symmetric system through mirror symmetry via Noether’s theorem when illuminated by a homogeneous light wave. Therefore, it is still very challenging to break the mirror symmetry and generate a lateral optical force (LOF) in the rotationally symmetric system. Here, we report a general dynamic action in the SO (2) rotationally symmetric system, originating from the polarization-tuned mirror symmetry breaking (MSB) of the light scattering. We demonstrate theoretically and experimentally that MSB can be generally applied to the SO (2) rotationally symmetric system and tuned sinusoidally by polarization orientation, leading to a highly tunable and highly efficient LOF (9.22 pN/mW/μm −2 ) perpendicular to the propagation direction. The proposed MSB mechanism and LOF not only complete the sets of MSB of light-matter interaction and non-conservative force only using a plane wave but also provide extra polarization manipulation freedom. In a SO (2) rotationally symmetric system, a general polarization-tuned mirror symmetry breaking mechanism was reported to highly efficiently generate a lateral optical force, enriching the optical manipulation mechanism for mirror-symmetric objects.

The therapeutic efficacy of 5-fluorouracil (5-FU) is often reduced by the development of drug resistance. We observed significant upregulation of lipocalin 2 (LCN2) expression in a newly established 5-FU-resistant colorectal cancer (CRC) cell line. In this study, we demonstrated that 5-FU-treated CRC cells developed resistance through LCN2 upregulation caused by LCN2 promoter demethylation and that feedback between LCN2 and NF-κB further amplified LCN2 expression. High LCN2 expression was associated with poor prognosis in CRC patients. LCN2 attenuated the cytotoxicity of 5-FU by activating the SRC/AKT/ERK-mediated antiapoptotic program. Mechanistically, the LCN2-integrin β3 interaction enhanced integrin β3 stability, thus recruiting SRC to the cytomembrane for autoactivation, leading to downstream AKT/ERK cascade activation. Targeting LCN2 or SRC compromised the growth of CRC cells with LCN2-induced 5-FU resistance. Our findings demonstrate a novel mechanism of acquired resistance to 5-FU, suggesting that LCN2 can be used as a biomarker and/or therapeutic target for advanced CRC.

The implementation of sponge cities in China modifies the hydrological conditions of the underlying surface, effectively alleviating the urban heat island effect. However, in planning and construction, heat island mitigation targets are difficult to quantify and lack quantitative design and evaluation methods. To address this issue, two planning schemes were proposed based on sponge city management and control indicators. The WRF-UCM model was used to conduct numerical simulations of the current conditions (case 1) and the sponge city planning schemes (cases 2 and 3), analyzing the impact of sponge city initiatives on the mitigation of the heat island effect. The results indicated that by changing the structure of the underlying surface and increasing the water content of the underlying surface, the sponge city affects the urban energy distribution process and regional horizontal advection pattern. This not only reduces heat accumulation within the urban area but also suppresses regional convection during high-temperature periods, thereby mitigating the urban heat island effect. Moreover, different schemes following the same sponge city design requirements have varying impacts on urban microclimate elements and heat island distributions. Notably, a higher subsurface water content yields a more pronounced inhibition of the heat island effect. Finally, a sponge city planning method with the consideration of heat island mitigation was proposed, facilitating pre-simulation optimization and decision-making in sponge city planning.

Coagulopathy is a critical pathophysiological mechanism of acute pancreatitis (AP), arising from the complex interplay between innate immune, endothelial cells and platelets. Although initially beneficial for the host, uncontrolled and systemic activation of coagulation cascade in AP can lead to thrombotic and hemorrhagic complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as disseminated intravascular coagulation. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1. Finally, increased fibrin generation and impaired break down lead to deposition of (micro) vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. Despite the high burden of coagulopathy that have a negative impact on AP patients’ prognosis, there is no effective treatment yet. Although a variety of anticoagulants drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by hemorrhagic complications. Future studies are called to unravel the pathophysiologic mechanisms involved in coagulopathy in AP, and to test novel therapeutics block coagulopathy in AP.

Evapotranspiration (E), a pivotal phenomenon inherent to hydrological and thermal dynamics, assumes a position of utmost importance within the intricate framework of the water–energy nexus. However, the quantitative study of E on a large scale for the “Grain for Green” projects under the backdrop of climate change is still lacking. Consequently, this study examined the interannual variations and spatial distribution patterns of E, transpiration (Et), and soil evaporation (Eb) in the Northern Foot of Yinshan Mountain (NFYM) between 2000 and 2020 and quantified the contributions of climate change and vegetation greening to the changes in E, Et, and Eb. Results showed that E (2.47 mm/a, p < 0.01), Et (1.30 mm/a, p < 0.01), and Eb (1.06 mm/a, p < 0.01) all exhibited a significant increasing trend during 2000–2020. Notably, vegetation greening emerged as the predominant impetus underpinning the augmentation of both E and Eb, augmenting their rates by 0.49 mm/a and 0.57 mm/a, respectively. In terms of Et, meteorological factors emerged as the primary catalysts, with temperature (Temp) assuming a predominant role by augmenting Et at a rate of 0.35 mm/a. Temp, Precipitation (Pre), and leaf area index (LAI) collectively dominated the proportional distribution of E, accounting for shares of 32.75%, 28.43%, and 25.01%, respectively. Within the spectrum of predominant drivers influencing Et, Temp exerted the most substantial influence, commanding the largest proportion at 33.83%. For Eb, the preeminent determinants were recognized as LAI and Temp, collectively constituting a substantial portion of the study area, accounting for 32.10% and 29.50%, respectively. The LAI exerted a pronounced direct influence on the Et, with no significant effects on E and bare Eb. Wind speed (WS) had a substantial direct impact on both E and Et. Pre exhibited a strong direct influence on E, Et, and Eb. Relative humidity (RH) significantly affected E directly. Temp primarily influenced Eb indirectly through radiation (Rad). Rad exerted a significant direct inhibitory effect on Eb. These findings significantly advanced our mechanistic understanding of how E and its components in the NFYM respond to climate change and vegetation greening, thus providing a robust basis for formulating strategies related to regional ecological conservation and water resources management, as well as supplying theoretical underpinnings for constructing sustainable vegetation restoration strategies involving water resources in the region.

Precise modulation of the cell cycle via electromagnetic (EM) control presents a groundbreaking approach for cancer therapy, especially in the development of personalized treatment strategies. EM fields can precisely regulate key cellular homeostatic mechanisms such as proliferation, apoptosis, and repair by finely tuning parameters like frequency, intensity, and duration. This review summarizes the mechanisms through which EM fields influence cancer cell dynamics, highlighting recent developments in high-throughput electromagnetic modulation platforms that facilitate precise cell cycle regulation. Additionally, the integration of electromagnetic modulation with emerging technologies such as artificial intelligence, immunotherapy, and nanotechnology is explored, collectively enhancing targeting precision, immune activation, and therapeutic efficacy. A systematic analysis of existing clinical studies indicates that EM modulation technology significantly overcomes key challenges such as tumor heterogeneity, microenvironment complexity, and treatment-related adverse effects. This review summarizes the prospects of electromagnetic modulation in clinical translation and future research directions, emphasizing its critical potential as a core element in individualized and multimodal cancer treatment strategies.