MiR-30a-5p isoform -1|1 promotes the progression of gastric cancer by inhibiting TMEM66 and reducing intratumoral cytotoxic T cells.

Gastric cancer is histologically classified into the intestinal subtype, which forms tubular structures, and the aggressive diffuse subtype, characterized by rapid invasion and poor prognosis. The variety and quantity of miRNA isoforms between different histological subtypes of gastric cancer were unknown. Through systematic filtering, we found that more diverse miR-30a-5p isoforms was present in the diffuse subtype of gastric cancer, and was associated with patients' worse survival independent of tumor stage based on the TCGA miRNA-seq data. Among all nine isoforms of miR-30a-5p, miR-30a-5p -1|1 was more abundant than the archetype of miR-30a-5p. Higher expression of miR-30a-5p -1|1 was observed in patients with advanced tumor stage and poor survival. Furthermore, miR-30a-5p -1|1 could promote the metastasis of gastric cancer cells both in vitro and in vivo by down-regulating TMEM66. In clinical samples, decreased expression of TMEM66 was characteristic of gastric cancer, and the low level of TMEM66 correlated with deceased CD8 positive cells in the tumor microenvironment probably due to decreased cytokines production. In conclusion, the variety of miR-30a-5p isoforms correlates with worse survival in gastric cancer patients. Moreover, miR-30a-5p -1|1 could promote gastric cancer metastasis by inhibiting TMEM66 and the infiltration of intratumoral CD8 positive cells.

An ultrasound-based ensemble machine learning model for the preoperative classification of pleomorphic adenoma and Warthin tumor in the parotid gland.

OBJECTIVES: The preoperative classification of pleomorphic adenomas (PMA) and Warthin tumors (WT) in the parotid gland plays an essential role in determining therapeutic strategies. This study aims to develop and validate an ultrasound-based ensemble machine learning (USEML) model, employing nonradiative and noninvasive features to differentiate PMA from WT. METHODS: A total of 203 patients with histologically confirmed PMA or WT who underwent parotidectomy from two centers were enrolled. Clinical factors, ultrasound (US) features, and radiomic features were extracted to develop three types of machine learning model: clinical models, US models, and USEML models. The diagnostic performance of the USEML model, as well as that of physicians based on experience, was evaluated and validated using receiver operating characteristic (ROC) curves in internal and external validation cohorts. DeLong's test was used for comparisons of AUCs. SHAP values were also utilized to explain the classification model. RESULTS: The USEML model achieved the highest AUC of 0.891 (95% CI, 0.774-0.961), surpassing the AUCs of both the US (0.847; 95% CI, 0.720-0.932) and clinical (0.814; 95% CI, 0.682-0.908) models. The USEML model also outperformed physicians in both internal and external validation datasets (both p < 0.05). The sensitivity, specificity, negative predictive value, and positive predictive value of the USEML model and physician experience were 89.3%/75.0%, 87.5%/54.2%, 87.5%/65.6%, and 89.3%/65.0%, respectively. CONCLUSIONS: The USEML model, incorporating clinical factors, ultrasound factors, and radiomic features, demonstrated efficient performance in distinguishing PMA from WT in the parotid gland. CLINICAL RELEVANCE STATEMENT: This study developed a machine learning model for preoperative diagnosis of pleomorphic adenoma and Warthin tumor in the parotid gland based on clinical, ultrasound, and radiomic features. Furthermore, it outperformed physicians in an external validation dataset, indicating its potential for clinical application. KEY POINTS: • Differentiating pleomorphic adenoma (PMA) and Warthin tumor (WT) affects management decisions and is currently done by invasive biopsy. • Integration of US-radiomic, clinical, and ultrasound findings in a machine learning model results in improved diagnostic accuracy. • The ultrasound-based ensemble machine learning (USEML) model consistently outperforms physicians, suggesting its potential applicability in clinical settings.

Fusobacterium nucleatum promotes the early occurrence of esophageal cancer through upregulation of IL-32/PRTN3 expression.

Previous studies have shown that gastrointestinal microbiome is associated with the development of esophageal cancer, but the relationship and molecular mechanism between esophageal microbiota and the early development of esophageal cancer remain unclear. Here, we found that Lactobacillus, Escherichia-Shigella, Rikenellaceae-RC9-gut-group, Morganella, and Fusobacterium were more abundant in early-stage esophageal cancer (EEC) tissues compared with normal esophageal tissues. The abundance of bacteria such as Prevotella, Fusobacterium, Porphyromonas, Actinobacillus, and Neisseria in advanced esophageal cancer (AEC) was higher than that in EEC. Then, we further verified that Fusobacterium nucleatum (Fn) was enriched in EEC tissues and that its abundance increased with the progression of esophageal cancer by FISH and RT-PCR. Next, we demonstrated that Fn promoted the proliferation of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. Finally, we confirmed that Fn promoted ESCC proliferation by upregulating the expression of interleukin (IL)-32/proteinase 3 (PRTN3) and then activating the PI3K/AKT signaling pathway. In conclusion, Fn promoted the early development of ESCC by upregulating the expression of IL-32/PRTN3 and thereby activating the PI3K/AKT signaling pathway. A better understanding of the molecular mechanism of Fn in early esophageal cancer may contribute to the development of early screening markers to diagnose ESCC and provide new targets for treatment.

A Novel Multicolor Flow Cytometry Scoring System for the Diagnosis and Prognostic Stratification of Myelodysplastic Syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) are a class of myeloid neoplasms featuring inefficient maturation and differentiation of hematopoietic cells, blood cytopenia, and a high risk of leukemia onset. The diagnosis of MDS remains a challenging task owing to its complexity, heterogeneity, and the lack of specific characteristics. METHODS: To look for an easy and inexpensive diagnostic method for MDS, we tried to establish an FCM scoring systems (FCSS) with a combination of antibodies for diagnosis and prognostic stratification of MDS. This FCSS adopted four parameters; i.e., the frequency of myeloblasts in nucleated cells, the ratio between pro-B cells and CD117+ cells, the ratio of CD45 mean fluorescence intensity between lymphocytes and myeloblasts, and the ratio of SSC peak values between mature granulocytes and lymphocytes. RESULTS: We tested the correlation between the total FCSS score with conventional IPSS-R. Additionally, the correlation between the score of each FCSS parameter and IPSS-R was also evaluated. We found that total FCSS score had a positive correlation with IPSS-R, while FCSS parameter 1 and 4 were also correlated with IPSS-R. Furthermore, this FCSS had a sound sensitivity and specificity in the diagnosis of MDS. CONCLUSIONS: The FCSS represents a convenient and affordable approach for the diagnosis and prognostic stratification of MDS.

Fusobacterium nucleatum facilitates ulcerative colitis through activating IL-17F signaling to NF-κB via the upregulation of CARD3 expression.

Accumulating evidence links Fusobacterium nucleatum with ulcerative colitis (UC). The mechanism by which F. nucleatum promotes intestinal inflammation in UC remains poorly defined. Here, we first examined the abundance and impact of F. nucleatum on disease activity in UC tissues. Next, we isolated a strain of F. nucleatum from UC tissues and explored whether F. nucleatum aggravates the intestinal inflammatory response in vitro and in vivo. We also examined whether F. nucleatum infection involves the NF-κB or IL-17F signaling pathways. Our data showed that F. nucleatum was enriched in 51.78% of UC tissues and was correlated with the clinical course, clinical activity and refractory behavior of UC (p < 0.05). Furthermore, we demonstrated that F. nucleatum promoted intestinal epithelial damage and the expression of the inflammatory cytokines IL-1ß, Il-6, IL-17F and TNF-α. Mechanistically, F. nucleatum targeted caspase activation and recruitment domain 3 (CARD3) through NOD2 to activate the IL-17F/NF-κB pathway in vivo and in vitro. Thus, F. nucleatum orchestrates a molecular network involving CARD3 and IL-17F to control the UC process. Measuring and targeting F. nucleatum and its associated pathways will yield valuable insight into the prevention and treatment of UC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Comprehensive analysis of T-cell receptor repertoire in patients with acute coronary syndrome by high-throughput sequencing.

BACKGROUND: This study aims to investigate the T-cell receptor (TCR) repertoire in patients with acute coronary syndrome (ACS). METHODS: The TCR repertoires of 9 unstable angina patients (UA), 14 acute myocardial infarction patients (AMI) and 9 normal coronary artery (NCA) patients were profiled using high-throughput sequencing (HTS). The clonal diversity of the TCR repertoires in different groups was analyzed, as well as the frequencies of variable (V), diversity (D) and joining(J) gene segments. RESULTS: ACS patients including UA and AMI, showed reduced TCRß diversity than NCA patients. ACS patients presented higher levels of clonal expansion. The clonotype overlap of complementarity determining region 3(CDR3) was significantly varied between different groups. A total of 10 V genes and 1 J gene were differently utilized between ACS and NCA patients. We identified some shared CDR3 amino acid sequences that were presented in ACS but not in NCA patients. CONCLUSIONS: This study revealed the distinct TCR repertoires in patients with ACS and demonstrated the presence of disease associated T-cell clonotypes. These findings suggested a role of T cells in ACS and provided a new way to explore the mechanisms of ACS.

Invasive Fusobacterium nucleatum may play a role in the carcinogenesis of proximal colon cancer through the serrated neoplasia pathway.

The prevalence of invasive Fusobacterium nucleatum (Fn) within the serrated neoplasia pathway of the proximal colon has seldom been investigated. We examined the invasive Fn and bacterial biofilms in 35 proximal hyperplastic polyps (HPs), 33 sessile serrated adenomas (SSAs), 48 proximal colorectal cancers (CRCs) and 10 matched metastatic lymph nodes using 16S rRNA fluorescence in situ hybridization (FISH). Samples of normal mucosa, traditional adenomas (TAs), distal HPs, distal CRCs and matched lymph nodes with or without metastases were used as controls. The prevalence of invasive Fn within proximal HPs (65.7%) and SSAs (78.8%) were significantly higher than that of proximal TAs (28.9%) and distal TAs (24.4%; p < 0.05). Invasive Fn was detected in markedly more proximal CRCs (89.6%) than in distal CRCs (42.2%; p < 0.05). Moreover, invasive Fn was detected in a significantly higher proportion of matched metastatic lymph nodes (100%) than that within nonmetastatic lymph nodes (40.0%; p < 0.001). Bacterial biofilms were found on 52.1% of proximal CRCs, 55.6% of distal CRCs and 48.5% of SSAs. Biofilms were positive for Fn in 47.9% of proximal CRCs, 48.9% of distal CRCs and 27.3% of SSAs. However, the presence of Fn in biofilms was not related to invasive Fn within colorectal tissues (p = 0.415). Invasive Fn may play a role in the carcinogenesis of proximal colon developing via the serrated neoplasia pathway, but might have a less important role in the TA-carcinoma sequence. Bacterial biofilms may not contribute to the invasion of Fn into tumor tissues.

Comprehensive characterization of immunogenic cell death in acute myeloid leukemia revealing the association with prognosis and tumor immune microenvironment.

BACKGROUND: This study aimed to explore the clinical significance of immunogenic cell death (ICD) in acute myeloid leukemia (AML) and its relationship with the tumor immune microenvironment characteristics. It also aimed to provide a potential perspective for bridging the pathogenesis of AML and immunological research, and to provide a theoretical basis for precise individualized treatment of AML patients. METHODS: Firstly, we identified two subtypes associated with ICD by consensus clustering and explored the biological enrichment pathways, somatic mutations, and tumor microenvironment landscape between the ICD subtypes. Additionally, we developed and validated a prognostic model associated with ICD-related genes. Finally, we conducted a preliminary exploration of the construction of disease regulatory networks and prediction of small molecule drugs based on five signature genes. RESULTS: Differentially expressed ICD-related genes can distinguish AML into subgroups with significant differences in clinical characteristics and survival prognosis. The relationship between the ICD- high subgroup and the immune microenvironment was tight, showing significant enrichment in immune-related pathways such as antibody production in the intestinal immune environment, allograft rejection, and Leishmaniasis infection. Additionally, the ICD- high subtype showed significant upregulation in a variety of immune cells such as B_cells, Macrophages_M2, Monocytes, and T_cells_CD4. We constructed a prognostic risk feature based on five signature genes (TNF, CXCR3, CD4, PIK3CA and CALR), and the time-dependent ROC curve confirmed the high accuracy in predicting the clinical outcomes. CONCLUSION: There is a strong close relationship between the ICD- high subgroup and the immune microenvironment. Immunogenicity-related genes have the potential to be a prognostic biomarker for AML.

VEPH1 suppresses the progression of gastric cancer by regulating the Hippo-YAP signalling pathway.

BACKGROUND: Ventricular zone-expressed PH domain-containing protein homologue 1 (VEPH1) is a recently discovered intracellular adaptor protein that plays an important role in human development. It has been reported that VEPH1 is closely related to the process of cellular malignancy, but its role in gastric cancer has not been elucidated. This study investigated the expression and function of VEPH1 in human gastric cancer (GC). METHODS: We performed qRT‒PCR, Western blotting, and immunostaining assays in GC tissue samples to evaluate VEPH1 expression. Functional experiments were used to measure the malignancy of GC cells. A subcutaneous tumorigenesis model and peritoneal graft tumour model were established in BALB/c mice to determine tumour growth and metastasis in vivo. RESULTS: VEPH1 expression is decreased in GC and correlates with the overall survival rates of GC patients. VEPH1 inhibits GC cell proliferation, migration, and invasion in vitro and suppresses tumour growth and metastasis in vivo. VEPH1 regulates the function of GC cells by inhibiting the Hippo-YAP signalling pathway, and YAP/TAZ inhibitor-1 treatment reverses the VEPH1 knockdown-mediated increase in the proliferation, migration and invasion of GC cells in vitro. Loss of VEPH1 is associated with increased YAP activity and accelerated epithelial-mesenchymal transition (EMT) in GC. CONCLUSION: VEPH1 inhibited GC cell proliferation, migration, and invasion in vitro and in vivo and exerted its antitumour effects by inhibiting the Hippo-YAP signalling pathway and EMT process in GC.

Unique Plant Resources and Distribution Patterns in the Valley Forest of the Irtysh River Basin.

The river valley forests of the Irtysh River Basin are a germplasm bank of Salicaceae species and rare plant resources in China, and the distribution varies with the river and is highly distinctive. However, there is a dearth of systematic research on the characteristics of plant resources. In this study, a comprehensive investigation was conducted in the trunk stream and six tributaries with valley forest distribution in the Irtysh River Basin, and 244 quadrats were set up. The analysis focused on the composition of the flora and resource characteristics. The results reveal the following: (1) The valley forests of the Irtysh River Basin contain 256 species of plants belonging to 57 families and 178 genera, among which 19 species of trees, 23 species of shrubs, and 214 species of herbs were investigated. (2) Among the identified species, 226 (88.67%) were recognized as resource plants, with medicinal plants being the most abundant (176 species, 68.75% of the total). (3) The distribution patterns of trees, shrubs, and herbs of each resource type vary across rivers. Elevation drop, river length, and river distance all significantly affect the number of specie. This study elucidated the current status and distributional characteristics of plant resources in the valley forests of the Irtysh River Basin, which is essential for both biodiversity conservation and sustainable resource utilization.

The Predictive Value of ACR TI-RADS Classification for Central Lymph Node Metastasis of Papillary Thyroid Carcinoma: A Retrospective Study.

BACKGROUND: The aim of this retrospective study was to evaluate the risk factors for central lymph node metastasis (CLNM) in papillary thyroid carcinoma (PTC), according to the guidelines of the 2017 Thyroid Imaging Report and Data System (TI-RADS) published by the American College of Radiology (ACR). METHODS: This study included a retrospective analysis of 844 patients with PTC who were pathologically diagnosed, treated with central lymph node dissection, and divided into CLNM and nonmetastatic groups. Univariate and multivariate analyses were performed to determine the relationship between the TI-RADS score and CLNM. RESULTS: Among 844 patients, 439 developed CLNM, with a metastasis rate of 52% and a TI-RADS score of 9.42 ± 2.262, which were higher than those of the non-CLNM group (P < 0.05). Univariate analysis demonstrated that the sex, location, maximum diameter of the nodule, multifocality, margin, shape, calcification, and TI-RADS score were related to CLNM (P < 0.05 for all). However, multivariate logistic regression analysis demonstrated that female, maximum diameter of the nodule, multifocality, a taller-than-wide shape, and high TI-RADS score were the independent risk factors for CLNM (P < 0.05 for all). CONCLUSION: The TI-RADS score combined with sex, nodule size, shape, and multifocality has a certain predictive effect on CLNM, which can provide a reference to the clinicians for further treatment strategies.

Erratum: Fusobacterium nucleatum Promotes Metastasis in Colorectal Cancer by Activating Autophagy Signaling via the Upregulation of CARD3 Expression: Erratum.

[This corrects the article DOI: 10.7150/thno.38870.].

Dicer deletion in hepatocytes promotes macrophages M1 polarization through dysregulated miR-192-3p/IGF2 in non-alcoholic steatohepatitis and hepatocellular carcinoma.

Macrophages plays a vital role in the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), but the polarization of macrophages was not consistent in previous reports and the contribution of hepatocytes to macrophage polarization is not clear. Here, we show that in clinical NASH and HCC samples, impaired Dicer activity was common and correlated with increased M1-like macrophages. Mice with Dicer deletion in hepatocytes could induce macrophages M1 polarization either in the development of NASH under high fat diet feeding, or in the carcinogenesis of HCC after DEN treatment. In hepatic cells, Dicer deletion delivered distinct lipid profile and increased lipid oxidation. Mechanically, Dicer deletion caused declined miR-192-3p and increased IGF2 in hepatocytes. Restoring miR-192-3p could suppress IGF2 and inhibit macrophage infiltration in the liver tissue, as well as reduce the lipid de novo synthesis and peroxidation. Overall, our data highlights the central role of Dicer-associated miR-192-3p in the etiopathogenesis of macrophage M1 polarization in NASH and HCC.

m6A Modification Mediates Mucosal Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease.

Accumulating evidence links m6A modification with immune infiltration. However, the correlation and mechanism by which m6A modification promotes intestinal immune infiltration in inflammatory bowel disease (IBD) is unknown. Here, genomic information from IBD tissues was integrated to evaluate disease-related m6A modification, and the correlation between the m6A modification pattern and the immune microenvironment in the intestinal mucosa was explored. Next, we identified hub genes from the key modules of the m6Acluster and analyzed the correlation among the hub genes, immune infiltration, and therapy. We found that IGF2BP1 and IGF2BP2 expression was decreased in Crohn's disease (CD) tissues and that IGF2BP2 was decreased in ulcerative colitis (UC) tissues compared with normal tissues (P < 0.05). m6Acluster2, containing higher expressions of IL15, IL16, and IL18, was enriched in M0 macrophage, M1 macrophage, native B cells, memory B cells, and m6Acluster1 with high expression of IL8 and was enriched in resting dendritic and plasma cells (P < 0.05). Furthermore, we reveal that expression of m6A phenotype-related hub genes (i.e., NUP37, SNRPG, H2AFZ) was increased with a high abundance of M1 macrophages, M0 macrophages, and naive B cells in IBD (P < 0.01). Immune checkpoint expression in the genecluster1 with higher expression of hub genes was increased. The anti-TNF therapeutic response of patients in genecluster1 was more significant, and the therapeutic effect of CD was better than that of UC. These findings indicate that m6A modification may affect immune infiltration and therapeutic response in IBD. Assessing the expression of m6A phenotype-related hub genes might guide the choice of IBD drugs and improve the prediction of therapeutic response to anti-TNF therapy.

ASPM is a Novel Candidate Gene Associated with Colorectal Cancer Cell Growth.

Colorectal cancer (CRC) is one of the most prevalent diseases worldwide; however, the molecular mechanisms involved in CRC remain unclear. Thus, we aimed to explore a novel biomarker for CRC. In this study, we screened 361 differentially expressed genes; 152 downregulated genes; and 209 upregulated genes) through analysis of the GSE44861, GSE110223, GSE110224, and GSE113513 CRC datasets. Next, ASPM, CCNA2, CCNB1, CEP55, KIF20A, MAD2L1, MELK, RRM2, TOP2A, TPX2, TRIP13, and TTK were identified as hub genes associated with the cell cycle in CRC through comprehensive bioinformatics analysis using the Cytoscape and Metascape software, the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and the Oncomine and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases. Furthermore, ASPM mRNA expression in CRC tissues was verified in Oncomine, The Cancer Genome Atlas and our data, and ASPM was found to be significantly upregulated in CRC tissues compared with that in the noncancer colon tissues. Functionally, we showed that overexpression of ASPM significantly promoted the proliferation and inhibited apoptosis; silencing of ASPM suppressed the proliferation of CRC cells by affecting the cell cycle G1/S transition by reducing cyclin E1 expression, and inducing apoptosis. Overall, our findings indicated that ASPM plays a crucial role in the regulation of CRC cell proliferation, and ASPM is a potential candidate diagnostic tool and therapeutic target for CRC.

Corrigendum: Fusobacterium nucleatum Activates Endoplasmic Reticulum Stress to Promote Crohn's Disease Development via the Upregulation of CARD3 Expression.

[This corrects the article DOI: 10.3389/fphar.2020.00106.].

Development and Validation of a LASSO Prediction Model for Better Identification of Ischemic Stroke: A Case-Control Study in China.

BACKGROUND: Timely diagnosis of ischemic stroke (IS) in the acute phase is extremely vital to achieve proper treatment and good prognosis. In this study, we developed a novel prediction model based on the easily obtained information at initial inspection to assist in the early identification of IS. METHODS: A total of 627 patients with IS and other intracranial hemorrhagic diseases from March 2017 to June 2018 were retrospectively enrolled in the derivation cohort. Based on their demographic information and initial laboratory examination results, the prediction model was constructed. The least absolute shrinkage and selection operator algorithm was used to select the important variables to form a laboratory panel. Combined with the demographic variables, multivariate logistic regression was performed for modeling, and the model was encapsulated within a visual and operable smartphone application. The performance of the model was evaluated on an independent validation cohort, formed by 304 prospectively enrolled patients from June 2018 to May 2019, by means of the area under the curve (AUC) and calibration. RESULTS: The prediction model showed good discrimination (AUC = 0.916, cut-off = 0.577), calibration, and clinical availability. The performance was reconfirmed in the more complex emergency department. It was encapsulated as the Stroke Diagnosis Aid app for smartphones. The user can obtain the identification result by entering the values of the variables in the graphical user interface of the application. CONCLUSION: The prediction model based on laboratory and demographic variables could serve as a favorable supplementary tool to facilitate complex, time-critical acute stroke identification.

SATB2 Defect Promotes Colitis and Colitis-associated Colorectal Cancer by Impairing Cl-/HCO3- Exchange and Homeostasis of Gut Microbiota.

BACKGROUND: SATB2 is a diagnostic biomarker and a favourable prognostic marker for colorectal cancer [CRC], but its role in colitis and colitis-associated colorectal cancer [CAC] is unknown. METHODS: Colitis was induced in intestinal epithelial-specific Satb2 knockout [Satb2 IEC-KO] and control mice using dextran sulphate sodium [DSS]. RNA-seq analysis was performed on colonic tissues, and 16S rDNA-Seq on faecal bacterial DNA from Satb2 IEC-KO and control mice. Immunohistochemistry and flow cytometry were performed to reveal the proportions of different immune cells. Chromatin immunoprecipitation [ChIP] and luciferase reporter were applied to show the regulatory role of SATB2 on SLC26A3, of which the Cl-/HCO3- exchange activity was measured fluorometrically by the pHi-sensitive dye. Bacteroides were detected by fluorescence in situ hybridisation [FISH] on colonic tissue. RESULTS: Satb2 IEC-KO mice suffered from intestinal epithelial damage spontaneously, and developed more severe colitis and CAC. The expression of SLC26A3 correlated well with SATB2 revealed by RNA-seq and The Cancer Genome Atlas [TCGA] data, and was governed by SATB2 confirmed by ChIP and luciferase reporter experiments. Decreased intestinal flora diversity was seen in Satb2 IEC-KO mice. Bacteroides were more abundant and could colonise into the inner layer of colonic mucosa in Satb2 IEC-KO mice. Faecal microbiome transplantation from Satb2 IEC-KO mice aggravated colitis and M1 macrophages infiltration. CONCLUSIONS: SATB2 plays a vital role in maintaining intestinal homeostasis, and its deficiency promotes the development of colitis and CAC by influencing the intestinal luminal environment and gut flora.

A single-cell atlas of liver metastases of colorectal cancer reveals reprogramming of the tumor microenvironment in response to preoperative chemotherapy.

Metastasis is the primary cause of cancer-related mortality in colorectal cancer (CRC) patients. How to improve therapeutic options for patients with metastatic CRC is the core question for CRC treatment. However, the complexity and diversity of stromal context of the tumor microenvironment (TME) in liver metastases of CRC have not been fully understood, and the influence of stromal cells on response to chemotherapy is unclear. Here we performed an in-depth analysis of the transcriptional landscape of primary CRC, matched liver metastases and blood at single-cell resolution, and a systematic examination of transcriptional changes and phenotypic alterations of the TME in response to preoperative chemotherapy (PC). Based on 111,292 single-cell transcriptomes, our study reveals that TME of treatment-naïve tumors is characterized by the higher abundance of less-activated B cells and higher heterogeneity of tumor-associated macrophages (TAMs). By contrast, in tumors treated with PC, we found activation of B cells, lower diversity of TAMs with immature and less activated phenotype, lower abundance of both dysfunctional T cells and ECM-remodeling cancer-associated fibroblasts, and an accumulation of myofibroblasts. Our study provides a foundation for future investigation of the cellular mechanisms underlying liver metastasis of CRC and its response to PC, and opens up new possibilities for the development of therapeutic strategies for CRC.

Fusobacterium nucleatum Activates Endoplasmic Reticulum Stress to Promote Crohn's Disease Development via the Upregulation of CARD3 Expression.

There is increasing evidence that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are associated with Crohn's disease (CD), but the specific mechanism by which F. nucleatum promotes CD development is unclear. Here, we first examined the abundance of F. nucleatum and its effects on CD disease activity and explored whether F. nucleatum aggravated intestinal inflammation and promoted intestinal mucosal barrier damage in vitro and in vivo. Our data showed that F. nucleatum was enriched in 41.21% of CD tissues from patients and was correlated with the clinical course, clinical activity, and refractory behavior of CD (P < 0.05). In addition, we found that F. nucleatum infection is involved in activating the endoplasmic reticulum stress (ERS) pathway during CD development to promote intestinal mucosal barrier destruction. Mechanistically, F. nucleatum targeted caspase activation and recruitment domain 3 (CARD3) to activate the ERS pathway and promote F. nucleatum-mediated mucosal barrier damage in vivo and in vitro. Thus, F. nucleatum coordinates a molecular network involving CARD3 and ERS to control the CD process. Measuring and targeting F. nucleatum and its associated pathways will provide valuable insight into the prevention and treatment of CD.