Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) ...represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A
dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell-cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A
DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Nucleotide‐based drugs, such as antisense oligonucleotides (ASOs), have unique advantages in treating human diseases as they provide virtually unlimited ability to target any gene. However, their ...clinical translation faces many challenges, one of which is poor delivery to the target tissue in vivo. This problem is particularly evident in solid tumors. Here, liposomes are functionalized with a tumor‐homing and ‐penetrating peptide, iRGD, as a carrier of an ASO against androgen receptor (AR) for prostate cancer treatment. The iRGD‐liposomes exhibit a high loading efficiency of AR‐ASO, and an efficient knockdown of AR gene products is achieved in vitro, including AR splice variants. In vivo, iRGD‐liposomes significantly increase AR‐ASO accumulation in the tumor tissue and decrease AR expression relative to free ASOs in prostate tumors established as subcutaneous xenografts. Similar results are obtained with intra‐tibial xenografts modeling metastasis to bones, the predominant site of metastasis for prostate cancer. In treatment studies, iRGD‐liposomes markedly improve the AR‐ASO efficacy in suppressing the growth of both subcutaneous xenografts and intra‐tibial xenografts. The inhibitory effect on tumor growth is also significantly prolonged by the delivery of the AR‐ASO in the iRGD‐liposomes. Meanwhile, iRGD‐liposomes does not increase ASO accumulation or toxicity in healthy organs. Overall, a delivery system that can significantly increase ASO accumulation and efficacy in solid tumors is provided here. These benefits are achieved without significant side effects, providing a way to increase the antitumor efficacy of ASOs.
A peptide (iRGD)‐functionalized liposomal system is generated to improve the delivery of antisense oligonucleotides (ASOs) into solid tumors. This system increases the tumor accumulation and vascular penetration of an ASO against androgen receptor (AR) in castration‐resistant prostate cancer and bone metastases. This results in an increase in short‐ and long‐term antitumor efficacy of AR‐ASO against both primary tumors and metastasis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Femtosecond lasers enable flexible and thermal‐damage‐free ablation of solid materials and are expected to play a critical role in high‐precision cutting, drilling, and shaping of electronic chips, ...display panels, and industrial parts. Although the potential applications are theoretically predicted, true 3D nano‐sculpturing of solids such as glasses and crystals, has not yet been demonstrated, owing to the technical challenge of negative cumulative effects of surface changes and debris accumulation on the delivery of laser pulses and subsequent material removal during direct‐write ablation. Here, a femtosecond laser‐induced cavitation‐assisted true 3D nano‐sculpturing technique based on the ingenious combination of cavitation dynamics and backside ablation is proposed to achieve stable clear‐field point‐by‐point material removal in real time for precise 3D subtractive fabrication on various difficult‐to‐process materials. As a result, 3D devices including free‐form silica lenses, micro‐statue with vivid facial features, and rotatable sapphire micro‐mechanical turbine, all with surface roughness less than 10 nm are readily produced. The true 3D processing capability can immediately enable novel structural and functional micro‐nano optics and non‐silicon micro‐electro‐mechanical systems based on various hard solids.
From technical points to cavitation mechanism, this work demonstrates an unprecedented laser nano‐subtractive technology based on continuous controllable precise ablation with both true 3D and wide material applicability, especially for hard crystals. This versatile technology will surely become a standard manufacturing method for various 3D devices in the micro‐nano field.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•Prenatal maternal stress may be related to congenital heart disease in offspring.•Stress and stressful life events may increase risk of congenital heart disease.•No evidence of associations were ...found for maternal anxiety and depression.•More support and care should be given to mothers with stress during pregnancy.
Background The relationship between maternal psychological stress during pregnancy and risk of congenital heart disease (CHD) in offspring is still unclear. We conducted a meta-analysis to quantitatively evaluate the association.
Methods Literature search was performed through May 2020 using PubMed and Web of Science databases. Observational studies evaluating the associations of maternal psychological stress including stress, stress life events, anxiety and depression with CHD risk in offspring were eligible for the study.
Results Ten case-control studies with 16,382 CHD cases and 1,812,999 non-CHD controls were included in the meta-analysis. Four studies assessed the association between maternal stress during pregnancy and CHD risk in offspring. The pooled odds ratio (OR) was 2.11 (95%CI: 1.62, 2.74) for those mothers with stress during pregnancy. Six studies assessed the association between maternal stressful life events during pregnancy and CHD risk in offspring. The pooled OR was 1.86 (95%CI: 1.29, 2.68) for those mothers exposed to stressful life events during pregnancy. Maternal anxiety and depression may not be associated with CHD risk in offspring. The pooled ORs were 1.42 (95%CI: 0.53, 3.77) and 2.10 (95%CI: 0.46, 9.59) for the maternal anxiety and depression during pregnancy, respectively.
Limitations Residual confounding, heterogeneity and publication bias may exist, which may limit the interpretation of the results.
Conclusion Maternal stress and stressful life events during pregnancy may be associated with higher risk of CHD in offspring, but such association was not observed for other mental health exposures such as anxiety and depression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Optical crystals are ideal materials for complex functional and durable optical components, but their good stability and hardness bring about difficulties in high‐precision machining and require ...surface roughness below λ/10. Femtosecond laser ablation is a widely applicable processing method indifferent to material types, but its 3D fabrication capability is limited by the accumulation of ablated debris and rough ablated surface. This work demonstrates a universal and flexible technology for the fabrication of crystalline micro‐optics with required shape and surface roughness for the most demanding optical phase control. The cavitation‐assisted ablation by a direct laser writing mode is followed by a high‐temperature treatment to remove the rough non‐crystalline layer caused by ablation. The annealing at temperatures below the melting point of the crystal reduces the roughness down to ≈2 nm without changing the structure shape. This virtue of maintaining the designed shape without change, which is impossible during thermal morphing of 3D surfaces of glasses, allows for a previously unavailable flexibility of surface finish for the most demanding optical micro‐optical elements made in this study. This universal technology with nanoscale resolution and free‐form 3D manufacturing capability is applicable for various crystals and provides a new way to fabricate micro‐/integrated‐optics and nonlinear optical elements.
A universal processing technology with nanoscale resolution and free‐form 3D manufacturing capability based on femtosecond laser ablation and thermal morphing is applicable for various crystals and provides a new way for the fabrication of micro‐/integrated‐optics and nonlinear optical elements. A variety of high‐quality sapphire micro‐optical elements with precise phase control are shown.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Small clinical trials have reported that low-frequency repetitive transcranial magnetic stimulation (rTMS) might improve language recovery in patients with aphasia after stroke. However, no ...systematic reviews or meta-analyses studies have investigated the effect of rTMS on aphasia. The objective of this study was to perform a meta-analysis of studies that explored the effects of low-frequency rTMS on aphasia in stroke patients.
We searched PubMed, CENTRAL, Embase, CINAHL, ScienceDirect, and Journals@Ovid for randomized controlled trials published between January 1965 and October 2013 using the keywords "aphasia OR language disorders OR anomia OR linguistic disorders AND repetitive transcranial magnetic stimulation OR rTMS". We used fixed- and random-effects models to estimate the standardized mean difference (SMD) and a 95% CI for the language outcomes.
Seven eligible studies involving 160 stroke patients were identified in this meta-analysis. A significant effect size of 1.26 was found for the language outcome severity of impairment (95% CI = 0.80 to 1.71) without heterogeneity (I2 = 0%, P = 0.44). Further analyses demonstrated prominent effects for the naming subtest (SMD = 0.52, 95% CI = 0.18 to 0.87), repetition (SMD = 0.54, 95% CI = 0.16 to 0.92), writing (SMD = 0.70, 95% CI = 0.19 to 1.22), and comprehension (the Token test: SMD = 0.58, 95% CI = 0.07 to 1.09) without heterogeneity (I2 = 0%). The SMD of AAT and BDAE comprehension subtests was 0.32 (95% CI = -0.08 to 0.72) with moderate heterogeneity (I2 = 32%,P = 0.22). The effect size did not change significantly even when any one trial was eliminated. None of the patients from the 7 included articles reported adverse effects from rTMS.
Low-frequency rTMS with a 90% resting motor threshold that targets the triangular part of the right inferior frontal gyrus (IFG) has a positive effect on language recovery in patients with aphasia following stroke. Further well-designed studies with larger populations are required to ascertain the long-term effects of rTMS in aphasia treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 ...knockout mice were significantly resistant to oxidative stress such as H2O2‐induced injury and hypoxia/reoxygenation‐induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs‐mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang‐II)‐induced cardiac hypertrophy. Following 14 days of Ang‐II infusion with osmotic mini‐pumps, a comparable hypertension was generated in both of CD38 knockout and wild‐type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild‐type mice compared with CD38 knockout mice. Consistently, RNAi‐induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang‐II‐stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca2+ release induced by Ang‐II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca2+‐NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Femtosecond laser machining has been widely used for fabricating arbitrary 2.5 dimensional (2.5D) structures. However, it suffers from the problems of low fabrication efficiency and high surface ...roughness when processing hard materials. To solve these problems, we propose a dry‐etching‐assisted femtosecond laser machining (DE‐FsLM) approach in this paper. The fabrication efficiency could be significantly improved for the formation of complicated 2.5D structures, as the power required for the laser modification of materials is lower than that required for laser ablation. Furthermore, the surface roughness defined by the root‐mean‐square improved by an order of magnitude because of the flat interfaces of laser‐modified regions and untreated areas as well as accurate control during the dry‐etching process. As the dry‐etching system is compatible with the IC fabrication process, the DE‐FsLM technology shows great potential for application in the device integration processing industry.
Dry‐etching‐assisted femtosecond laser machining technology is proposed for fabricating complex microstructures. As an example, a silicon concave microlens array could be successfully fabricated. The morphology of microstructures could be flexibly adjusted by controlling the activation and passivation effect. The combination of the three‐dimensional fabrication property of femtosecond lasers with the precision processing of dry etching would develop a new fabrication technology.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•Co-exposure to high copper and tetracycline increased the abundance of ARGs in the mouse guts.•Abnormal copper and/or tetracycline exposure significantly affected the community ...structure of the mouse gut microbiota.•Abnormal intake of copper and/or tetracyclines increased the enrichment of potential pathogens in the mouse guts and the pathogenic risk to public health.
The widespread use of copper and tetracycline as growth promoters in the breeding industry poses a potential threat to environmental health. Nevertheless, to the best of our knowledge, the potential adverse effects of copper and tetracycline on the gut microbiota remain unknown. Herein, mice were fed different concentrations of copper and/or tetracycline for 6 weeks to simulate real life–like exposure in the breeding industry. Following the exposure, antibiotic resistance genes (ARGs), potential pathogens, and other pathogenic factors were analyzed in mouse feces. The co-exposure of copper with tetracycline significantly increased the abundance of ARGs and enriched more potential pathogens in the gut of the co-treated mice. Copper and/or tetracycline exposure increased the abundance of bacteria carrying either ARGs, metal resistance genes, or virulence factors, contributing to the widespread dissemination of potentially harmful genes posing a severe risk to public health. Our study provides insights into the effects of copper and tetracycline exposure on the gut resistome and potential pathogens, and our findings can help reduce the risks associated with antibiotic resistance under the One Health framework.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this paper, we first propose a linearized method for solving the tensor complementarity problem. The subproblems of the method can be solved by solving linear complementarity problems with a ...constant matrix. We show that if the initial point is appropriately chosen, then the generated sequence of iterates converges to a solution of the problem monotonically. We then propose a lower-dimensional equation method and establish its monotone convergence. The subproblems of the method are lower-dimensional systems of linear equations. At last, we do numerical experiments to test the proposed methods. The results show the efficiency of the proposed methods.
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