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Fluorescent light-up probes based on aggregation-induced emission (AIE)-active molecules have recently attracted great research interest due to the intelligent fluorescence activation mechanism and high sensitivity. In this work, an AIE-silica nanosphere (SiO 2 NP)-based label-free fluorescent aptasensor for the sensitive “turn-on” detection of prostate-specific antigen (PSA) is reported for the first time. The positively charged amino-functionalized SiO 2 NPs were used as efficient nanocapturer to electrostatically adsorb single-stranded PSA aptamer (PA) to form SiO 2 NP-PA nanocomposite as well as adsorb negatively charged tetraphenylethylene derivative 3 (TPE3) to form AIE-SiO 2 NP nanocomposite. The binding of the aptamer to the target PSA could induce a rigid aptamer conformation, resulting in the release of the PA away from the surface of SiO 2 NPs. This made the AIE molecules TPE3 aggregate on the SiO 2 NP surface and emit high fluorescence. With the advantages of simple design and rapid responses, the proposed aptasensor showed high sensitivity and selectivity for PSA with a detection limit of 0.5 ng/mL. The aptasensor was further applied in human serum samples with satisfactory results. Given its versatility, high selectivity, and sensitivity, the proposed method could be extended to other targets by varying the recognition probes. Graphical abstract An AIE-SiO 2 NP-based label-free fluorescent aptasensor for the sensitive “turn-on” detection of PSA is reported for the first time

Background Deciphering intra‐ and inter‐tumoural heterogeneity is essential for understanding the biology of gastric cancer (GC) and its metastasis and identifying effective therapeutic targets. However, the characteristics of different organ‐tropism metastases of GC are largely unknown. Methods Ten fresh human tissue samples from six patients, including primary tumour and adjacent non‐tumoural samples and six metastases from different organs or tissues (liver, peritoneum, ovary, lymph node) were evaluated using single‐cell RNA sequencing. Validation experiments were performed using histological assays and bulk transcriptomic datasets. Results Malignant epithelial subclusters associated with invasion features, intraperitoneal metastasis propensity, epithelial–mesenchymal transition‐induced tumour stem cell phenotypes, or dormancy‐like characteristics were discovered. High expression of the first three subcluster‐associated genes displayed worse overall survival than those with low expression in a GC cohort containing 407 samples. Immune and stromal cells exhibited cellular heterogeneity and created a pro‐tumoural and immunosuppressive microenvironment. Furthermore, a 20‐gene signature of lymph node‐derived exhausted CD8+ T cells was acquired to forecast lymph node metastasis and validated in GC cohorts. Additionally, although anti‐NKG2A (KLRC1) antibody have not been used to treat GC patients even in clinical trials, we uncovered not only malignant tumour cells but one endothelial subcluster, mucosal‐associated invariant T cells, T cell‐like B cells, plasmacytoid dendritic cells, macrophages, monocytes, and neutrophils may contribute to HLA‐E‐KLRC1/KLRC2 interaction with cytotoxic/exhausted CD8+ T cells and/or natural killer (NK) cells, suggesting novel clinical therapeutic opportunities in GC. Additionally, our findings suggested that PD‐1 expression in CD8+ T cells might predict clinical responses to PD‐1 blockade therapy in GC. Conclusions This study provided insights into heterogeneous microenvironment of GC primary tumours and organ‐specific metastases and provide support for precise diagnosis and treatment. 1) Single‐cell RNA‐seq of organ‐specific metastasis (liver, peritoneum, ovary, lymph node) in GC was conducted. 2) Single‐cell analysis determined phenotypes and functions of four malignant epithelial subtypes in GC. 3) A 20‐gene signature of lymph node‐derived exhausted CD8+ T cells might forecast lymph node metastasis, and targeting HLA‐E‐KLRC1/KLRC2 signaling severs as a novel clinical therapeutic opportunity for GC.

A novel ratiometric fluorescence nanoprobe based on carbon dots (CDs) and Cu nanoclusters (CuNCs) was designed for the label-free determination of uric acid (UA). The metal-organic framework (MOF) encapsulated CuNCs (ZIF-CuNC), and nitrogen-doped CDs can self-assemble into well-defined spherical nanocomposites (CD@ZIF-CuNC) due to physical adsorption. Under the excitation wavelength of 360 nm, the CD@ZIF-CuNC nanocomposites exhibit two evident intrinsic emissions peaked at 460 nm (CDs) and 620 nm (ZIF-CuNC), respectively. In the presence of H 2 O 2 , the fluorescence of CD@ZIF-CuNC at 620 nm is quenched remarkably within 1 min, while little effect on the emission at 460 nm is observed. Therefore, taking the fluorescence at 620 nm as the report signal and 460 nm as the reference signal, ratiometric quantitative determination of H 2 O 2 was achieved with a linear range of 1–100 μM and a detection limit of 0.30 μM. The CD@ZIF-CuNC nanoprobe was successfully applied to the determination of UA that is catalyzed by uricase to produce H 2 O 2 , obtaining the linear range of 1–30 μM and the detection limit of 0.33 μM. Eventually, this strategy has been successfully applied to the determination of UA in human urine samples. Graphical abstract A novel and convenient CDs@ZIF-CuNCs-based nanoplatform was constructed for sensitive ratiometric fluorescence determination of UA.

Deregulation of the Wnt signaling pathway leads to colorectal cancer progression. Natural dietary compounds serve as promising candidates for development as chemopreventive agents by suppressing the Wnt/β-catenin signaling pathway. Physalis peruviana-derived 4βHWE showed a significant inhibitory activity with a calculated IC50 of 0.09 μΜ in a screening of novel inhibitors of Wnt signaling with the dual-luciferase reporter assay. This study investigated the anti-tumor effect of 4βHWE and the potential Wnt signaling inhibitory mechanism. Both the western blot analysis and immunofluorescence assay showed that 4βHWE promoted the phosphorylation and degradation of β-catenin and the subsequent inhibition of its nuclear translocation to attenuate the endogenous Wnt target gene expression in colorectal cancer (CRC) cells. The cell viability assay indicated that 4βHWE preferentially inhibited the proliferation of CRC compared with CCD-841-CoN, a normal human colonic epithelial cell line. 4βHWE-mediated G0/G1 cell cycle arrest and apoptosis induction contributed to the suppression of the proliferation of CRC in the cell cycle and Annexin V-FITC/Propidium Iodide apoptosis analysis. Moreover, in vivo, 4βHWE dramatically inhibited tumor growth in HCT116 xenografts by attenuating the Wnt/β-catenin signaling pathway. In conclusion, our study suggested that 4βHWE could be of potential use in anti-tumor agent development as a novel Wnt signaling inhibitor.

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the premetastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients, and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the premetastatic niche. Mechanistically, cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase. In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that, by modifying glucose utilization by recipient premetastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression. Wang and colleagues report that cancer-cell-derived extracellular vesicles that contain miR-122 reprogram glucose metabolism of premetastatic niche cells to alter nutrient availability and promote metastasis.

BackgroundDisturbed self-regulation, taste reward, as well as somatosensory and visuospatial processes were thought to drive binge eating and purging behaviors that characterize bulimia nervosa. Although studies have implicated a central role of the striatum in these dysfunctions, there have been no direct investigations on striatal functional connectivity in bulimia nervosa from a network perspective.MethodsWe calculated the functional connectivity of striatal subregions based on the resting-state functional Magnetic Resonance Imaging data of 51 bulimia nervosa patients and 53 healthy women.ResultsCompared with the healthy women, bulimia nervosa patients showed increased positive functional connectivity in bilateral striatal nuclei and thalamus for nearly all of the striatal subregions, and increased negative functional connectivity in bilateral primary sensorimotor cortex and occipital areas for both ventral striatum and putamen subregions. Only for the putamen subregions, we observed reduced negative functional connectivity in the prefrontal (bilateral superior and middle frontal gyri) and parietal (right inferior parietal lobe and precuneus) areas. Several striatal connectivities with occipital and primary sensorimotor cortex significantly correlated with the severity of bulimia.ConclusionsThe findings indicate bulimia nervosa-related alterations in striatal functional connectivity with the dorsolateral prefrontal cortex supporting self-regulation, the subcortical striatum and thalamus involved in taste reward, as well as the visual occipital and sensorimotor regions mediating body image, which contribute to our understanding of neural circuitry of bulimia nervosa and encourage future therapeutic developments for bulimia nervosa by modulating striatal pathway.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses. Pancreatic ductal adenocarcinoma must adapt to a nutrient-poor microenvironment. Here, the authors show that miR-135 accumulates in response to glutamine deprivation and inhibits aerobic glycolysis by targeting phosphofructokinase-1, thereby redirecting glucose carbon to the TCA cycle and allowing pancreatic cancer cells survival.

Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. In melanoma, tumour cells often experience low glutamine levels, which promote cell dedifferentiation. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in a transgenic melanoma mouse model, and increases sensitivity to a BRAF inhibitor. Metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine in tumours and its downstream metabolite, αKG, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome in tumours. Our data further demonstrate that increase in intra-tumoural αKG concentration drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide evidence that glutamine supplementation can serve as a potential dietary intervention to block melanoma tumour growth and sensitize tumours to targeted therapy via epigenetic reprogramming. The availability of nutrients within the tumour microenvironment can influence tumour growth. Here, the authors find that, in a melanoma mouse model, mice fed a high glutamine diet have reduced tumour growth, increased sensitivity to Braf inhibitors and elevated a-ketoglutarate levels.

Objective To analyze the clinical characteristics of patients with overweight acute type A aortic dissection, and to explore the risk factors of acute kidney injury in patients with overweight acute type A aortic dissection. Methods From March 2019 to February 2022, the clinical data of 71 patients with acute type a aortic dissection diagnosed by CTA and undergoing surgical treatment with BMI > 24 in the First People's Hospital of Yunnan Province were retrospectively analyzed, and analyzed by univariate and logistic multivariate analysis methods. Results The mean BMI of all included patients was 27.23, The mean surface area of all included human populations was 1.833. The mean age of all patients was (52.06 ± 10.71) years old, and 35 patients developed acute kidney injury after surgery. Multi-factor Logistics regression analysis confirmed the risk factors for postoperative acute kidney injury in overweight patients with acute type A aortic dissection, including gender, CPB transit time and intraoperative infusion of suspended red blood cells. Seven patients in the AKI group died in hospital after surgery and two patients died in the non-AKI group. Conclusions Among patients with overweight acute Type A aortic dissection, the incidence of AKI is 49.30%. According to multi-factor Logistics regression analysis, gender, CPB transit time and intraoperative suspended red blood cell volume are independent risk factors for postoperative acute kidney injury in patients with overweight acute Type A aortic dissection.

The authors describe a fluorescent “turn-on” assay for detection of uric acid (UA) based on the use of graphene quantum dots coated with a shell of silver (GQD@Ag). The fluorescence of the GQDs is quenched by the silver shell. However, if the silver shell was removed via etching with H 2 O 2 (which is produced by uricase catalyzed oxidation of UA), the fluorescence of the GQDs is restored. The resulting increase in fluorescence at 466 nm depends directly on the concentration of H 2 O 2 , which, in turn, depends on the concentration of UA. The method allows UA to be quantitated with a 2 μM detection limit. It was applied to the analysis of human urine samples and exhibited satisfactory results. The method is cost-effective, sensitive and selective for UA. In our perception, it provides a useful tool in clinical analysis and may be extended to other assays based on the use of oxidases. Graphical abstract Schematic of the reduction of Ag(I) and the growth of a silver shell on the surface of graphene quantum dots (GQDs) to form a GQD@Ag nanocomposite whose fluorescence is quenched. Uricase catalyzes the oxidation of uric acid (UA) to produce allantoin and H 2 O 2 which etches the silver shell. This results in the release of GQDs and increased fluorescence, allowing quantitative analysis of UA.