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.
Ultrareliable and low-latency communication (URLLC) is a prerequisite for the successful implementation of the Internet of Controllable Things. In this article, we investigate the potential of deep ...reinforcement learning (DRL) for joint subcarrier-power allocation to achieve low latency and high reliability in a general form of device-to-device (D2D) networks, where each subcarrier can be allocated to multiple D2D pairs and each D2D pair is permitted to utilize multiple subcarriers. We first formulate the above problem as a Markov decision process and then propose a double deep <inline-formula> <tex-math notation="LaTeX">Q </tex-math></inline-formula>-network (DQN)-based resource allocation algorithm to learn the optimal policy in the absence of full instantaneous channel state information (CSI). Specifically, each D2D pair acts as a learning agent that adjusts its own subcarrier-power allocation strategy iteratively through interactions with the operating environment in a trial-and-error fashion. Simulation results demonstrate that the proposed algorithm achieves near-optimal performance in real time. It is worth mentioning that the proposed algorithm is especially suitable for cases where the environmental dynamics are not accurate and the CSI delay cannot be ignored.
Thrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can ...release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated cofactor V (FVa), and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragment 1 (F1) and fragment 2 (F2) specifically to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa, which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin F1 + F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit patients with sepsis (n = 144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in factor VIII (FVIII)– and FIX-deficient plasma, as well as in FVIII-deficient mice. In summary, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation and correcting coagulation factor deficiency.
•Histones substitute FVa in an alternative prothrombinase that generates thrombin without phospholipids to propagate DIC.•Histones significantly reduce FXa requirement for initiation of thrombin generation to enable coagulation in hemophilia plasma.
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•Vegetation in China showed a significant greening trend from 2001 to 2020.•Differences in the EVI patterns along four climate zones were characterized.•EVI was more sensitive to ...rainfall in the tropics and temperate regions.•This study is significant for the scientific management of cross climate zone ecosystems.
Vegetation growth is sensitive to climate change. The complex climate types of China pose great challenges to the sustainable management of vegetation on global change. Therefore, this study used Enhanced Vegetation Index (EVI) as an indicator to explore the spatiotemporal dynamics of vegetation and their driving factors in different climatic zones of China to provide theoretical support for sustainable vegetation management in different climate zones in the future. The results showed that vegetation exhibited considerable clustering patterns in the country, with high and low values concentrated in the eastern and western regions, respectively. From 2001 to 2020, both at regional and pixel scales, vegetation in China showed a significant greening trend. EVI displayed a noticeable increase within temperate and subtropical areas. The only exception is observed in the eastern coastal area of the North China Plain and Yangtze River Delta region, which experienced evident degradation trend. During this period, China's climate showed an overall trend towards warming and humidification with drying trends observed mainly over the western regions. The impact of climate changes resulted in EVI dynamics that vary over time and space. The vegetation change in China was mainly derived by changes in precipitation and radiation rather than temperature, especially in temperate and subfrigid regions. Precipitation was the main driving factor for vegetation greening in tropical and temperate regions, while radiation and temperature were the dominant climate factor for vegetation greening in subfrigid and subtropical regions, respectively. When precipitation was no longer a limiting factor for vegetation growth, the effect of temperature or radiation increases. In addition, the positive impact of precipitation on plant growth in temperate regions was much greater than that of radiation and temperature, and this difference was much greater than in tropical, subtropical, and subfrigid regions.
Artificial cardiovascular devices, such as vascular stents, artificial valves, and artificial hearts, can rebuild human cardiovascular functionalities via rebuilding the blood flow passing through ...these devices. To evaluate the red blood cells (RBCs) damage induced by a non-physiological blood flow in these devices, many hemolysis models have been proposed, of which the most popular one is a power function model. However, it was found that the newly obtained experimental data often did not match the existing power function model. In addition, the experimental period was usually short and the summarized power function model cannot reflect the RBCs damage after long-term exposure to shear stress. To address this issue, in this study a shear device was established on a torque rheometer; the changes of plasma free hemoglobin (FHB) of sheep blood under the shear stress from 10 to 70 Pa and exposure time from 5 to 30 min were recorded and compared. The results showed that as the shear stress and exposure time increased, FHB also increased, but the increase rate gradually decreased. As a result, after undergoing high shear stress or a long period of exposure time, FHB eventually became stable. Obviously, the existing power function model cannot describe this FHB change. In the current study, we used a sigmoidal logistic function model to describe the FHB increment upon the increase of shear stress and long exposure time. The results showed that the proposed model can provide better predictions of hemolysis, particularly in these cases under long exposure time.
Abstract 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.
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.
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