Cancer-secreted exosomal miRNAs are emerging mediators of cancer-stromal cross-talk in the tumor environment. Our previous miRNAs array of cervical squamous cell carcinoma (CSCC) clinical specimens ...identified upregulation of miR-221-3p. Here, we show that miR-221-3p is closely correlated with peritumoral lymphangiogenesis and lymph node (LN) metastasis in CSCC. More importantly, miR-221-3p is characteristically enriched in and transferred by CSCC-secreted exosomes into human lymphatic endothelial cells (HLECs) to promote HLECs migration and tube formation in vitro, and facilitate lymphangiogenesis and LN metastasis in vivo according to both gain-of-function and loss-of-function experiments. Furthermore, we identify vasohibin-1 (VASH1) as a novel direct target of miR-221-3p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of VASH1 could respectively rescue and simulate the effects induced by exosomal miR-221-3p. Importantly, the miR-221-3p-VASH1 axis activates the ERK/AKT pathway in HLECs independent of VEGF-C. Finally, circulating exosomal miR-221-3p levels also have biological function in promoting HLECs sprouting in vitro and are closely associated with tumor miR-221-3p expression, lymphatic VASH1 expression, lymphangiogenesis, and LN metastasis in CSCC patients. In conclusion, CSCC-secreted exosomal miR-221-3p transfers into HLECs to promote lymphangiogenesis and lymphatic metastasis via downregulation of VASH1 and may represent a novel diagnostic biomarker and therapeutic target for metastatic CSCC patients in early stages.
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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
COVID-19 is an infectious disease characterized by multiple respiratory and extrapulmonary manifestations, including gastrointestinal symptoms. Although recent studies have linked gut microbiota to ...infectious diseases such as influenza, little is known about the role of the gut microbiota in COVID-19 pathophysiology.
To better understand the host-gut microbiota interactions in COVID-19, we characterized the gut microbial community and gut barrier function using metagenomic and metaproteomic approaches in 63 COVID-19 patients and 8 non-infected controls. Both immunohematological parameters and transcriptional profiles were measured to reflect the immune response in COVID-19 patients.
Altered gut microbial composition was observed in COVID-19 patients, which was characterized by decreased commensal species and increased opportunistic pathogenic species. Severe illness was associated with higher abundance of four microbial species (i.e., Burkholderia contaminans, Bacteroides nordii, Bifidobacterium longum, and Blautia sp. CAG 257), six microbial pathways (e.g., glycolysis and fermentation), and 10 virulence genes. These severity-related microbial features were further associated with host immune response. For example, the abundance of Bu. contaminans was associated with higher levels of inflammation biomarkers and lower levels of immune cells. Furthermore, human-origin proteins identified from both blood and fecal samples suggested gut barrier dysfunction in COVID-19 patients. The circulating levels of lipopolysaccharide-binding protein increased in patients with severe illness and were associated with circulating inflammation biomarkers and immune cells. Besides, proteins of disease-related bacteria (e.g., B. longum) were detectable in blood samples from patients.
Our results suggest that the dysbiosis of the gut microbiome and the dysfunction of the gut barrier might play a role in the pathophysiology of COVID-19 by affecting host immune homeostasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
COVID‐19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID‐19 pathophysiology, we ...combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID‐19‐infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue‐specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN‐I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID‐19‐infected patients experiencing milder disease symptoms showed robust T‐cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS‐CoV‐2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID‐19.
SYNOPSIS
Proteomics, metabolomics and RNAseq data map immune responses in COVID‐19 patients with different disease severity, revealing molecular makers associated with disease progression and alterations of tissue‐specific proteins.
A multi‐omics profiling of the host response to SARS‐CoV2 infection in 66 clinically diagnosed and laboratory confirmed COVID‐19 patients and 17 uninfected controls.
Significant correlations between multi‐omics data and key clinical parameters.
Alteration of tissue‐specific proteins and exRNAs.
Enhanced activation of immune responses is associated with COVID‐19 pathogenesis.
Biomarkers to predict COVID‐19 clinical outcomes pending clinical validation as prospective marker.
Proteomics, metabolomics and RNAseq data map immune responses in COVID‐19 patients with different disease severity, revealing molecular makers associated with disease progression and alterations of tissue‐specific proteins.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Neutral eosin Y‐derived photoexcited states have been found to serve as photoacids and direct hydrogen atom transfer (HAT) catalysts in the activation of glycals and C−H bonds, respectively. These ...studies pave the way for further use of eosin Y in photochemical synthesis.
New sides of eosin Y: Neutral eosin Y‐derived photoexcited states have been found to serve as photoacids and direct hydrogen atom transfer (HAT) catalysts in the activation of glycals and C−H bonds, respectively. These studies pave the way for further use of eosin Y in photochemical synthesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To explore the mechanisms through which hypoxic tumor microenvironment (TME) modulates the transition of tumor‐associated macrophages (TAMs). The migration ability of RAW264.7 macrophages was ...determined by transwell assay. Flow cytometric, western blot and immunofluorescence analyses of CD206 further validated the M2 polarization of macrophages. Immunofluorescence, western blot and qRT‐PCR were performed to detect the expression of neuropilin‐1 (Nrp‐1) and carbonic anhydrase IX (CAIX). An intermittent hypobaric hypoxia (IH) animal model was established to evaluate the role of hypoxia in activating M2‐like TAMs in vivo. We also used immunohistochemistry to analyze the association between CAIX, CD163+ macrophages and Nrp‐1 in a series of 72 human cervical cancer specimens. We found that the hypoxic cervical TME educated the recruited macrophages to transform into the M2 phenotype. Nrp‐1 expression was significantly increased in hypoxia‐primed cervical cancer cells. Blocking Nrp‐1 expression prevented hypoxic cells from recruiting and polarizing macrophages towards the M2 phenotype. Hypoxia exposure significantly increased the expression of Nrp‐1 as well as the infiltration of macrophages in vivo. Consistently, immunochemical staining in serial tissue sections of cervical cancer revealed upregulated levels of Nrp‐1 in CAIX‐positive hypoxic regions along with a concurrent significant elevation of M2 macrophages. Nrp‐1 and M2‐like TAMs were related to the malignant properties of cervical cancer, such as the FIGO stage and lymph node metastasis. Nrp‐1 plays critical roles in hypoxic TME‐induced activation and pro‐tumoral effects of TAMs in cervical cancer. Interfering with Nrp‐1 may be a potential therapeutic strategy in treating cervical cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health
. Despite intense research efforts, how, when and where ...new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing
of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China
. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Exosomes are 30–120 nm endocytic membrane-derived vesicles that participate in cell-to-cell communication and protein and RNA delivery. Exosomes harbor a variety of proteins, nucleic acids, and ...lipids and are present in many and perhaps all bodily fluids. A significant body of literature has demonstrated that molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), hold great promise as novel biomarkers for clinical diagnosis. In this minireview, we summarize recent advances in the research of exosomal biomarkers and their potential application in clinical diagnostics. We also provide a brief overview of the formation, function, and isolation of exosomes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A highly enantioselective iridium‐ or ruthenium‐catalyzed intermolecular reductive amination/asymmetric hydrogenation relay with 2‐quinoline aldehydes and aromatic amines has been developed. A broad ...range of sterically tunable chiral N,N′‐diaryl vicinal diamines were obtained in high yields (up to 95 %) with excellent enantioselectivity (up to >99 % ee). The resulting chiral diamines could be readily transformed into sterically hindered chiral N‐heterocyclic carbene (NHC) precursors, which are otherwise difficult to access. The usefulness of this synthetic approach was further demonstrated by the successful application of one of the chiral vicinal diamines and chiral NHC ligands in a transition‐metal‐catalyzed asymmetric Suzuki–Miyaura cross‐coupling reaction and asymmetric ring‐opening cross‐metathesis, respectively.
In tandem: A direct and atom‐economical synthesis of enantiomerically enriched vicinal diamines by the title iridium‐ or ruthenium‐catalyzed reaction of 2‐quinoline aldehydes and aromatic amines is described (see scheme). The sterically tunable chiral diamine products provided a platform for the synthesis of bulky chiral NHC ligands and can themselves serve as ligands for asymmetric transition‐metal catalysis. IPA=isopropanol.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an ...essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe
efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
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