The long‐term outcome of gastric cancer (GC) patients remains unsatisfactory despite some recent improvements. Leukemia inhibitory factor (LIF) is a prognostic biomarker for some solid tumors, ...however its role in GC remains unknown. In this study, we demonstrated that LIF and LIF receptor (LIFR) are overexpressed in GC tissues and established that a correlation exists between them. LIF and LIFR expression are associated with tumor differentiation, lymphovascular invasion, tumor stage, lymph node metastasis, and pTNM stage, indicating that they may be useful prognostic factors. LIF promoted GC cell proliferation, colony formation, invasion, migration, and tumor growth; it also promoted cell cycle progression and inhibited apoptosis; and knocking out the LIFR gene reversed the effects of LIF. LIF inhibited the activity of the Hippo pathway, resulting in reduced phosphorylation of YAP, increased YAP nuclear translocation, and increased cell proliferation. Finally, silencing YAP mRNA expression suppressed cell proliferation. Overall, the results demonstrate that LIF promotes the malignant biological behavior of GC cells through LIFR–Hippo–YAP signaling. LIF may therefore be a useful biomarker for GC.
Our results establish a new LIF–LIFR–Hippo–YAP pathway that promotes gastric cancer (GC) proliferation, progression, migration, and invasion. Leukemia inhibitory factor (LIF) plays a crucial role in GC tumorigenesis and the development of an effective LIF or YAP antibody may represent a novel strategy to treat GC.
Intense infiltration of tumour-associated macrophages (TAMs) facilitates malignant growth of glioblastoma (GBM), but the underlying mechanisms remain undefined. Herein, we report that TAMs secrete ...abundant pleiotrophin (PTN) to stimulate glioma stem cells (GSCs) through its receptor PTPRZ1 thus promoting GBM malignant growth through PTN-PTPRZ1 paracrine signalling. PTN expression correlates with infiltration of CD11b
/CD163
TAMs and poor prognosis of GBM patients. Co-implantation of M2-like macrophages (MLCs) promoted GSC-driven tumour growth, but silencing PTN expression in MLCs mitigated their pro-tumorigenic activity. The PTN receptor PTPRZ1 is preferentially expressed in GSCs and also predicts GBM poor prognosis. Disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential. Moreover, blocking the PTN-PTPRZ1 signalling by shRNA or anti-PTPRZ1 antibody potently suppressed GBM tumour growth and prolonged animal survival. Our study uncovered a critical molecular crosstalk between TAMs and GSCs through the PTN-PTPRZ1 paracrine signalling to support GBM malignant growth, indicating that targeting this signalling axis may have therapeutic potential.
Efficient production of ammonia using environmentally friendly techniques under ambient conditions is crucial to renewable energy storage and industrial applications, and catalysts with new reaction ...pathways are highly desirable. In this work, black phosphorus (BP) is used as a metal‐free 2D catalyst for the photoelectrochemical (PEC) nitrogen reduction reaction (NRR). The electrode is fabricated by layer‐by‐layer assembly of BP nanosheets on an indium tin oxide substrate. The PEC NRR activity in the N2 saturated aqueous electrolyte without a sacrificial agent is excellent, as exemplified by an ammonia yield rate of 102.4 µg h−1 mgcat.−1 and Faradaic efficiency of 23.3% at −0.4 V, which are the best among nonmetal catalysts for synthesis of ammonia by photocatalysis and electrocatalysis. Furthermore, the BP electrode shows excellent stability after 6 consecutive cycles. The excellent PEC catalytic properties are attributed to the light excitation enhanced electrocatalytic process and that the external bias promoted photocatalytic process improves ammonia production synergistically. The results not only demonstrate the great potential of BP in PEC catalysis, but also identify a promising technique to produce ammonia under ambient conditions using solar energy and electric energy.
Black phosphorus (BP) is developed as a metal‐free 2D catalyst for the photoelectrochemical synthesis of ammonia at ambient conditions. The ammonia yield rate and Faradaic efficiency in acid electrolyte is determined as 102.4 µg h−1 mgcat.−1 and 23.3%, respectively. The excellent catalytic properties of BP are attributed to the synergistic effects of photoexcitation enhanced electrocatalysis and external bias promoted photocatalysis.
•Nitrate has a dual effect on sediment phosphorus release in shallow lakes•Nitrate can reduce sediment phosphorus release through oxidation•Nitrate can promote phosphorus release by stimulating ...phytoplankton growth•Alkaline phosphatase secreted by phytoplankton explains the phosphorus release•The effects of nitrate loading on sediment phosphorus release are dose-dependent
Phosphorus (P) release from sediment is a key process affecting the effectiveness of eutrophication mitigation. We hypothesized that high nitrate (NO3−) input may have dual effect on sediment P release: reduce the sediment P release by improving the oxidation of sediment or promote P release by stimulating the growth of phytoplankton and increase the decomposition rates and oxygen consumption at the sediment water interface. To test the effect of different NO3− concentrations, we conducted a three-month experiment in 15 cement tanks (1 m3), with five targeted concentrations of NO3−: control, 2 mg L−1, 5 mg L−1, 10 mg L−1, and 15 mg L−1. The results showed that: i) when NO3− was maintained at high levels: NO3−≥5–7 mg L−1 (range of median values), there was no effect of NO3− on net P release from the sediment, likely because the positive effects of NO3− (increasing oxidation) was counteracted by a promotion of phytoplankton growth. ii) after NO3− addition was terminated NO3− dropped sharply to a low level (NO3−≤0.4 mg L−1), followed by a minor P release in the low N treatments but a significant P release in the high N treatments, which likely reflect that the inhibition effect of NO3− on P release decreased, while the promotion effects at high NO3− concentrations continued. The results thus supported our hypotheses of a dual effect on sediment P release and suggest dose-dependent effect of NO3− loading on stimulating P release from the sediment, being clear at high NO3− exceeding 5–7 mg L−1.
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As a promising alternative platform for cellular immunotherapy, natural killer cells (NK) have recently gained attention as an important type of innate immune regulatory cell. NK cells can rapidly ...kill multiple adjacent cancer cells through non-MHC-restrictive effects. Although tumors may develop multiple resistance mechanisms to endogenous NK cell attack, in vitro activation, expansion, and genetic modification of NK cells can greatly enhance their anti-tumor activity and give them the ability to overcome drug resistance. Some of these approaches have been translated into clinical applications, and clinical trials of NK cell infusion in patients with hematological malignancies and solid tumors have thus far yielded many encouraging clinical results. CAR-T cells have exhibited great success in treating hematological malignancies, but their drawbacks include high manufacturing costs and potentially fatal toxicity, such as cytokine release syndrome. To overcome these issues, CAR-NK cells were generated through genetic engineering and demonstrated significant clinical responses and lower adverse effects compared with CAR-T cell therapy. In this review, we summarize recent advances in NK cell immunotherapy, focusing on NK cell biology and function, the types of NK cell therapy, and clinical trials and future perspectives on NK cell therapy.
Esophageal squamous cell carcinoma (ESCC) is highly malignant with highly invasive and metastatic capabilities and poor prognosis. It is believed that the ESCC cancer stem-like cells (ECSLCs) are ...critical for tumorigenicity, invasion and metastasis of ESCC. However, the properties of ECSLCs vary with different markers used in isolation, so that new and more effective markers of ECSLCs need to be identified. This study aimed to estimate the potentiality of Cripto-1 (CR-1) as an ECSLC surface marker and investigate the clinical significance of CR-1 expression in ESCC.
ESCC cells with CR-1
or CR-1
were obtained by flow cytometry then their self-renewal capability and tumorigenicity were compared by colony and limiting dilution sphere formation analysis in vitro and xenograft in nude mice in vivo, respectively. Knockdown of CR-1 expression in ESCC cells was conducted with short hairpin RNA. Cell migration and invasion were examined by scratch test and matrigel transwell assay, respectively. Metastatic capability of ESCC cells was assayed by a mouse tail vein metastasis model. The levels of CR-1 expression in cancerous and paired adjacent normal tissues were assessed by IHC and qRT-RCR.
CR-1
subpopulation of ESCC cells isolated by FACS expressed high level of genes related to stemness and epithelial-mesenchymal transition (EMT), and possessed high capacities of self-renewal, tumorigenesis, invasion and metastasis. Suppression of CR-1 expression significantly reduced the expression of stemness- and EMT-related genes and the capabilities of self-renewal in vitro, tumorigenicity and metastasis in vivo in ESCC cells. In the clinical ESCC specimens, the expression levels of CR-1 in cancerous tissues were positively correlated to TNM stage, invasive depth, and lymph node metastasis. Cox regression analysis indicated that CR-1 was an independent indicator of prognosis. The expression of CR-1 was found overlapping with aldehyde dehydrogenase 1A1 (ALDH1A1), an intracellular marker for ESCLCs, in ESCC cell lines and specimens.
CR-1 is a functional and cell surface ECSLC marker, and an independent prognostic indicator as well as a potential therapeutic target for ESCC.
Two dimensional (2D) nanoribbons constitute an emerging nanoarchitecture for advanced microelectronics and energy conversion due to the stronger size confinement effects compared to traditional ...nanosheets. Triclinic crystalline red phosphorus (cRP) composed by a layered structure is a promising 2D phosphorus allotrope and the tube‐like substructure is beneficial to the construction of nanoribbons. In this work, few‐layer cRP nanoribbons are synthesized and the effectiveness in the electrochemical nitrogen reduction reaction (NRR) is investigated. An iodine‐assisted chemical vapor transport (CVT) method is developed to synthesize circa 10 g of bulk cRP lumps with a yield of over 99 %. With the aid of probe ultrasonic treatment, high‐quality cRP microcrystals are exfoliated into few‐layer nanoribbons (cRP NRs) with large aspect ratios. As non‐metallic materials, cRP NRs are suitable for the electrochemical nitrogen reduction reaction. The ammonia yield is 15.4 μg h−1 mgcat.−1 at −0.4 V vs. reversible hydrogen electrode in a neutral electrolyte under ambient conditions and the Faradaic efficiency is 9.4 % at −0.2 V. Not only is cRP a promising catalyst, but also the novel strategy expands the application of phosphorus‐based 2D structures beyond that of traditional nanosheets.
Crystalline red phosphorus (cRP) with a layered structure are synthesized on a large scale by an efficient chemical vapor transport method and few‐layer 2D nanoribbons are exfoliated. Theoretical and experimental studies demonstrate that the cRP nanoribbons are promising in electrochemical nitrogen reduction in aqueous solutions under ambient conditions.
Hybridization of nitric oxide (NO) donors with known anti-cancer agents have been emerged as a strategy to achieve improved therapeutic effect and to overcome chemo-resistance in cancer therapy. In ...this study, furoxan moiety as an efficient NO donor was introduced to phenstatin, a microtubule-interfering agent (MIA), leading to the design and synthesis of a series of furoxan-based NO-releasing arylphenones derivatives. In biological evaluation, the synthesized compounds showed moderate to potent anti-tumor activities against several human cancer cell lines. Among them, compound 15h showed the most potent activities against both chemo-sensitive and resistant cancer cell lines with IC50 values ranging from 0.008 to 0.021 μM. Further mechanistic studies revealed that 15h worked as a bifunctional agent exhibiting both tubulin polymerized inhibition and NO-releasing activities, resulting in potent anti-angiogenesis, colony formation inhibition, cell cycle arrest and apoptosis induction effects. In the nude mice xenograft model, 15h significantly inhibited the paclitaxel-resistant tumor growth with low toxicity, demonstrating the promising potential for further preclinical evaluation as a therapeutic agent, particularly for the treatment of chemo-resistant cancers.
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•A series of furoxan-based NO-releasing arylphenones derivatives were synthesized and evaluated for anti-tumor activities.•Compound 15h showed enhanced anti-tumor activities on both chemo-sensitive and resistance cells in vitro and in vivo.•Compound 15h exhibited bifunctional effects on both tubulin polymerization and NO-releasing.
Macrophage-targeting therapies have become attractive strategies for immunotherapy. Deficiency of MARCO significantly inhibits tumor progression and metastasis in murine models of pancreatic cancer. ...However, the role of MARCO in patients with pancreatic cancer remains unclear. In the present study, we analyzed tumor-associated macrophage (TAM)-related changes using the Cancer Genome Atlas database. We observed a significant enrichment of M2 macrophages in pancreatic cancer tissues. We found that several pro-tumor markers are increased in cancer tissues, including CD163, CD206, SIRPα, LILRB1, SIGLEC10, AXL, MERTK, and MARCO. Crucially, MARCO is highly or exclusively expressed in pancreatic cancer across many types of solid tumors, suggesting its significant role in pancreatic cancer. Next, we investigated the expression of MARCO in relation to the macrophage marker CD163 in a treatment-naïve pancreatic cancer cohort after surgery (n = 65). MARCO and CD163 were analyzed using immunohistochemistry. We observed increased expression of CD163 and MARCO in pancreatic cancer tissues compared with paracancerous tissues. Furthermore, we observed a large variation in CD163 and MARCO expression in pancreatic cancer tissues among cases, suggesting the heterogeneous expression of these two markers among patients. Correlation to clinical data indicated a strong trend toward worse survival for patients with high CD163 and MARCO macrophage infiltration. Moreover, high CD163 and MARCO expression negatively affected the disease-free survival and overall survival rates of patients with pancreatic cancer. Univariate and multivariate analysis revealed that CD163 and MARCO expression was an independent indicator of pancreatic cancer prognosis. In conclusion, high CD163 and MARCO expression in cancer tissues is a negative prognostic marker for pancreatic cancer after surgery. Furthermore, anti-MARCO may be a novel therapy that is worth studying in depth.
We aimed to describe the heterogeneity in the clinical presentation of acute mountain sickness (AMS) and to identify its primary risk factors.
The participants (n = 163) received case report form ...questionnaires, and their heart rate (HR), oxygen saturation (SpO2), echocardiographic and transcranial Doppler variables, ability to perform mental and physical work, mood and psychological factors were assessed within 18 to 22 hours after arriving at 3700 m from sea level (500 m) by plane. First, we examined the differences in all variables between the AMS-positive and the AMS-negative groups. Second, an adjusted regression analysis was performed after correlation and principal component analyses.
The AMS patients had a higher diastolic vertebral artery velocity (Vd; p = 0.018), a higher HR (p = 0.006) and a lower SpO2. The AMS subjects also experienced poorer sleep quality, as quantified using the Athens Insomnia Scale (AIS). Moreover, the AMS population exhibited more negative mood states, including anxiety, depression, hostility, fatigue and confusion. Five principal components focused on diverse aspects were also found to be significant. Additionally, more advanced age (p = 0.007), a higher HR (p = 0.034), a higher Vd (p = 0.014), a higher AIS score (p = 0.030), a decreased pursuit aiming capacity (p = 0.035) and decreased vigor (p = 0.015) were risk factors for AMS.
Mood states play critical roles in the development of AMS. Furthermore, an elevated HR and Vd, advanced age, elevated AIS sores, insufficient vigor and decreased mental work capacity are independent risk factors for AMS.
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