Notes

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Metagenomic next-generation sequencing (mNGS) of microbial cell-free DNA (mcfDNA sequencing) is becoming an attractive diagnostic modality for infectious diseases, allowing broad-range pathogen detection, noninvasive sampling, and rapid diagnosis. At this key juncture in the translation of metagenomics into clinical practice, an integrative perspective is needed to understand the significance of emerging mcfDNA sequencing technology. In this review, we summarized the actual performance of the mcfDNA sequencing tests recently used in health care settings for the diagnosis of a variety of infectious diseases and further focused on the practice considerations (challenges and solutions) for improving the accuracy and clinical relevance of the results produced by this evolving technique. Such knowledge will be helpful for physicians, microbiologists and researchers to understand what is going on in this quickly progressing field of non-invasive pathogen diagnosis by mcfDNA sequencing and promote the routine implementation of this technique in the diagnosis of infectious disease. © The author(s).Rationale Multiple gastric cancer (MGC) is characterized by the presence of more than two different tumors in the stomach. However, the clonal relationship and carcinogenesis of MGC remain unclear. We investigated the clonal relationship and role of germline mutations in the carcinogenesis of MGC. Methods We gathered 16 multiple gastric cancer patients. Thirty-three tumor samples and sixteen normal gastric tissue or blood samples were obtained from January 2016 to December 2017. We also conducted analyses for 208 gastric cancer and 49 esophagogastric junction cancer (GC-EGJ) tumors from TCGA. DNA extraction from our samples was conducted for whole-exome sequencing (WES). Results Tumor mutation burden (TMB) was not statistically significant within database and our data in the GC-EGJ (P=0.0591) and GC groups (P=0.3113). The mutation spectrum and signatures also showed uniform distributions in GC and GC-EGJ groups within our data and TCGA database. Among sixteen patients, four were identified as monoclonal, in which 11, 10, 26 and 6 somatic mutations were shared within different tumors of P7, P8, P9 and P16, respectively. However, no common mutation between different tumors of the same patient was found among the other 12 patients. Kenpaullone After identifying predisposing genes, we found that germline MSH2 and NCOR2 mutations were significantly dominant in 8/12 and 10/12 of genetic MGC patients. Additionally, all patients were identified with MSH2 mutations in cancer samples of those genetic MGC patients. Taking genetic MGCs as a whole, we identified that TP53 were significantly mutated in 14 of 25 tumor samples. Main conclusions WES analyses are suggestive of monoclonal and polyclonal origin of MGC, which may promote the classification of MGC into genetic and metastatic MGC. For patients with genetic MGC, germline MSH2 X314_splice variants may contribute to carcinogenesis, thus prompting the consideration of more radical surgery and/or anti-PD-1/PD-L1 therapy. © The author(s).Cancer represents one of the main causes of death in the world; hence the development of more specific approaches for its diagnosis and treatment is urgently needed in clinical practice. Here we aim at providing a comprehensive review on the use of 2-dimensional materials (2DMs) in cancer theranostics. In particular, we focus on graphene-related materials (GRMs), graphene hybrids, and graphdiyne (GDY), as well as other emerging 2DMs, such as MXene, tungsten disulfide (WS2), molybdenum disulfide (MoS2), hexagonal boron nitride (h-BN), black phosphorus (BP), silicene, antimonene (AM), germanene, biotite (black mica), metal organic frameworks (MOFs), and others. The results reported in the scientific literature in the last ten years (>200 papers) are dissected here with respect to the wide variety of combinations of imaging methodologies and therapeutic approaches, including drug/gene delivery, photothermal/photodynamic therapy, sonodynamic therapy, and immunotherapy. We provide a unique multidisciplinary approach in discussing the literature, which also includes a detailed section on the characterization methods used to analyze the material properties, highlighting the merits and limitations of the different approaches. The aim of this review is to show the strong potential of 2DMs for use as cancer theranostics, as well as to highlight issues that prevent the clinical translation of these materials. Overall, we hope to shed light on the hidden potential of the vast panorama of new and emerging 2DMs as clinical cancer theranostics. © The author(s).Rationale Rheumatoid arthritis (RA) is a prototype of inflammatory arthritis in which synovial fibroblasts (SFs) play key roles in cartilage and bone destruction through tumor-like proliferation, migration, invasion and inflammation. This study aimed to research forkhead box protein C1 (FoxC1) and microRNA (miR)-141-3p, which modulate pathological changes in the synovial membrane, to find possible strategies for treating RA. Methods FoxC1, β-catenin and miR-141-3p gene expression in synovial tissues and SFs was quantified by real-time PCR; FoxC1 and β-catenin protein levels were evaluated by immunohistochemistry, immunofluorescence, and Western blotting. We transiently transfected human SFs with FoxC1 and β-catenin overexpression and silencing vectors and assessed proliferation, migration, invasion and inflammation by cell function and enzyme-linked immunosorbent assays. We also assessed downstream signaling activation using immunofluorescence, real-time PCR and Western blotting. Double luciferase, coimmunopror necrosis factor-α (TNF-α)) production and reduced anti-inflammatory cytokine (IL-10) levels in RASFs. FoxC1 bound to the β-catenin promoter, and β-catenin mediated the FoxC1-induced pathological changes. We also observed downregulated microRNA (miR)-141-3p expression in SFs from both RA patients and CIA rats and further found that miR-141-3p bound to the FoxC1 3'UTR and suppressed FoxC1 expression. Intra-ankle miR-141-3p agomir or FoxC1-specific siRNA injection hindered CIA development in rats. Conclusions FoxC1 and miR-141-3p participate in RA pathogenesis by mediating inflammation and SF proliferation, migration, and invasion and thus could be novel targets for RA therapy as a nonimmunosuppressive approach. © The author(s).Chronic kidney disease (CKD) is a serious healthcare dilemma, associated with specific changes in gut microbiota and circulating metabolome. Yet, the functional capacity of CKD microbiome and its intricate relationship with the host metabolism at different stages of disease are less understood. METHODS Here, shotgun sequencing of fecal samples and targeted metabolomics profiling of serum bile acids, short- and medium-chain fatty acids, and uremic solutes were performed in a cohort of CKD patients with different severities and non-CKD controls. RESULTS We identified that levels of 13 microbial species and 6 circulating metabolites were significantly altered across early to advanced stages or only in particular stage(s). Among these, Prevotella sp. 885 (decreased) was associated with urea excretion, while caproic acid (decreased) and p-cresyl sulfate (elevated) were positively and negatively correlated with the glomerular filtration rate, respectively. In addition, we identified gut microbial species linked to changes in circulating metabolites. Microbial genes related to secondary bile acid biosynthesis were differentially abundant at the early stage, while pathway modules related to lipid metabolism and lipopolysaccharide biosynthesis were enriched in the CKD microbiome at the advanced stage, suggesting that changes in microbial metabolism and host inflammation may contribute to renal health. Further, we identified metagenomic and metabolomic markers to discriminate cases of different severities from the controls, among which Bacteroides eggerthii individually was of particular value in early diagnosis. CONCLUSIONS Our dual-omics data reveal the connections between intestinal microbes and circulating metabolites perturbed in CKD, which may be of etiological and diagnostic importance. © The author(s).Rationale The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance. Methods Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib. ChIP-PCR assay forwith a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of KITLG and sorafenib resistance. Conclusion Our study reported a novel somatic mutation in OCT4 (c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns. © The author(s).We report the impact of notch-DLL4-based hereditary vascular heterogeneities on the enhanced permeation and retention (EPR) effect and plasmonic photothermal therapy response in tumors. Methods We generated two consomic rat strains with differing DLL4 expression on 3rd chromosome. These strains were based on immunocompromised Salt-sensitive or SSIL2Rγ- (DLL4-high) and SS.BN3IL2Rγ- (DLL4-low) rats with 3rd chromosome substituted from Brown Norway rat. We further constructed three novel SS.BN3IL2Rγ- congenic strains by introgressing varying segments of BN chromosome 3 into the parental SSIL2Rγ- strain to localize the role of SSIL2Rγ- DLL4 on tumor EPR effect with precision. We synthesized multimodal theranostic nanoparticles (TNPs) based on Au-nanorods which provide magnetic resonance imaging (MRI), X-ray, and optical contrasts to assess image guided PTT response and quantify host specific therapy response differences in tumors orthotopically xenografted in DLL4-high and -low strains. We tested recovery of therapy sensitivity of PTT resistant strains by employing anti-DLL4 conjugated TNPs in two triple negative breast cancer tumor xenografts. Results Host strains with high DLL4 allele demonstrated slightly increased tumor nanoparticle uptake but consistently developed photothermal therapy resistance compared to tumors in host strains with low DLL4 allele. Tumor micro-environment with low DLL4 expression altered the geographic distribution of nanoparticles towards closer proximity with vasculature which improved efficacy of PTT in spite of lower overall TNP uptake. Targeting TNPs to tumor endothelium via anti-DLL4 antibody conjugation improved therapy sensitivity in high DLL4 allele hosts for two triple negative human breast cancer xenografts. Conclusions Inherited DLL4 expression modulates EPR effects in tumors, and molecular targeting of endothelial DLL4 via nanoparticles is an effective personalized nanomedicine strategy. © The author(s).
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