Comprehensive Urinary Proteome Profiling Analysis Identifies Diagnosis and Relapse Surveillance Biomarkers for Bladder Cancer.

Bladder cancer (BCa) is the predominant malignancy of the urinary system. Herein, a comprehensive urine proteomic feature was initially established for the noninvasive diagnosis and recurrence monitoring of bladder cancer. 279 cases (63 primary BCa, 87 nontumor controls (NT), 73 relapsed BCa (BCR), and 56 nonrelapsed BCa (BCNR)) were collected to screen urinary protein biomarkers. 4761 and 3668 proteins were qualified and quantified by DDA and sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis in two discovery sets, respectively. Upregulated proteins were validated by multiple reaction monitoring (MRM) in two independent combined sets. Using the multi-support vector machine-recursive feature elimination (mSVM-RFE) algorithm, a model comprising 13 proteins exhibited good performance between BCa and NT with an AUC of 0.821 (95% CI: 0.675-0.967), 90.9% sensitivity (95% CI: 72.7-100%), and 73.3% specificity (95% CI: 53.3-93.3%) in the diagnosis test set. Meanwhile, an 11-marker classifier significantly distinguished BCR from BCNR with 75.0% sensitivity (95% CI: 50.0-100%), 81.8% specificity (95% CI: 54.5-100%), and an AUC of 0.784 (95% CI: 0.609-0.959) in the test cohort for relapse surveillance. Notably, six proteins (SPR, AK1, CD2AP, ADGRF1, GMPS, and C8A) of 24 markers were newly reported. This paper reveals novel urinary protein biomarkers for BCa and offers new theoretical insights into the pathogenesis of bladder cancer (data identifier PXD044896).

Improving the Oxygen Evolution Activity of Layered Double-Hydroxide via Erbium-Induced Electronic Engineering.

Layered double-hydroxide (LDH) has been considered an important class of electrocatalysts for the oxygen evolution reaction (OER), but the adsorption-desorption behaviors of oxygen intermediates on its surface still remain unsatisfactory. Apart from transition-metal doping to solve this electrocatalytic problem of LDH, rare-earth (RE) species have sprung up as emerging dopants owing to their unique 4f valence-electronic configurations. Herein, the Er is chosen as a RE model to improve OER activity of LDH via constructing nickel foam supported Er-doped NiFe-LDH catalyst (Er-NiFe-LDH@NF). The optimal Er-NiFe-LDH@NF exhibits a low overpotential (191 mV at 10 mA cm-2 ), high turnover frequency (0.588 s-1 ), and low activation energy (36.03 kJ mol-1 ), which are superior to Er-free sample. Electrochemical in situ Raman spectra reveal the facilitated transition of Ni-OH into Ni-OOH for promoted OER kinetics through the Er doping effect. Theoretical calculations demonstrate that the introduction of Er facilitates the spin crossover of valence electrons by optimizing the d band center of NiFe-LDH, which leads to the GO -GHO closer to the optimal activity of the kinetic OER volcano by balancing the bonding strength of *O and *OH. Moreover, the Er-NiFe-LDH@NF presents high practicability in electrochemical water-splitting devices with a low driving potential of and a well-extended driving period.

Enzymatic deamination of the epigenetic nucleoside N6-methyladenosine regulates gene expression.

N6-methyladenosine (m6A) modification is the most extensively studied epigenetic modification due to its crucial role in regulating an array of biological processes. Herein, Bsu06560, formerly annotated as an adenine deaminase derived from Bacillus subtilis 168, was recognized as the first enzyme capable of metabolizing the epigenetic nucleoside N6-methyladenosine. A model of Bsu06560 was constructed, and several critical residues were putatively identified via mutational screening. Two mutants, F91L and Q150W, provided a superiorly enhanced conversion ratio of adenosine and N6-methyladenosine. The CRISPR-Cas9 system generated Bsu06560-knockout, F91L, and Q150W mutations from the B. subtilis 168 genome. Transcriptional profiling revealed a higher global gene expression level in BS-F91L and BS-Q150W strains with enhanced N6-methyladenosine deaminase activity. The differentially expressed genes were categorized using GO, COG, KEGG and verified through RT-qPCR. This study assessed the crucial roles of Bsu06560 in regulating adenosine and N6-methyladenosine metabolism, which influence a myriad of biological processes. This is the first systematic research to identify and functionally annotate an enzyme capable of metabolizing N6-methyladenosine and highlight its significant roles in regulation of bacterial metabolism. Besides, this study provides a novel method for controlling gene expression through the mutations of critical residues.

Does Rectocele Repair Combined with Other Perineal Surgeries Affect Outcome Compared to Solo Rectocele Repair?

OBJECTIVES: Rectocele is common in female patients. To date, there is no literature comparing outcomes of rectocele repairs in combination with other perineal surgeries. We aim to analyze perioperative morbidity and mortality as well as long-term outcome of rectocele repair in combination with other perineal surgeries (RR combination) and compare this with solo rectocele repair (solo RR). DESIGN: The type of study was case-control. Data of patients who received solo rectocele repair or rectocele repair in combination with other perineal surgeries between January 2011 and December 2015 were identified and reviewed in a prospectively maintained and IRB-approved database. Ninety-eight patients were included, including 41 patients in the solo RR group and 57 patients in the RR combination group. The demographics, characteristics of patients, short-term complications, long-term complications, and morbidity of the 2 groups were observed. METHODS: The demographics, characteristics of patients, short-term complications, long-term complications, and morbidity of the 2 groups were compared, respectively. Covariate adjustment was analyzed by multivariate logistic and Cox regression analysis. RESULTS: Ninety-eight patients with a median age of 57 were included, involving 41 patients in the solo RR group and 57 patients in the RR combination group. Other than the operative approach (p < 0.01), demographics and preoperative characteristics of the 2 groups were comparable. All variables, including length of stay, estimated blood loss, self-limiting rectal bleeding, transfusion, urinary retention, rectal stricture, rectal and perineal infection, rectovaginal abscess, reoperation, effective resolution of obstructive defecation symptoms, residual symptoms rate, and recurrence rate, were comparable among the 2 groups except for operative time (p = 0.03). LIMITATIONS: This study is a single-center study, which may cause bias. In addition, the sample size is limited. Staging of rectocele and routine imaging studies were not performed. CONCLUSIONS: Rectocele repair in combination with other perineal surgeries is feasible, and outcomes are comparable with solo rectocele repair. Transanal versus transvaginal repairs appear to have no influence on outcomes.

Mutations in the notch signalling pathway are associated with enhanced anti-tumour immunity in colorectal cancer.

The Notch signalling pathway is involved in the development of several cancers, including colorectal cancer (CRC). However, whether mutations in this pathway could alter the CRC immunophenotype remains unknown. Here, we investigated the relationship between Notch signalling pathway mutations and the tumour immune microenvironment by analysing gene expression data from the GSE108989 single T cell RNA sequencing data set and The Cancer Genome Atlas (TCGA) data set. We found that Notch signalling pathway mutations were associated with an increased number of tumour-specific CD8+ T cells and decreased number of inhibitory regulatory T (Treg) cells, representing an enhanced anti-tumour response in the GSE108989 data set. In TCGA data set, we also found that Notch signalling pathway mutations were associated with enrichment of genes associated with immune activation pathways and higher expressions of PDCD1, GZMB and PRF1. Although Notch signalling pathway mutations did not affect the overall survival and disease-free survival of CRC patients, they were associated with earlier disease stages and lower rates of metastasis. These results demonstrated that Notch signalling pathway mutations can enhance anti-tumour immunity in CRC, as validated by the two data sets, suggesting that they may be promising biomarkers for immune checkpoint blockade therapies for CRC patients.

Intersphincteric Resection Versus Abdominoperineal Resection for Low Rectal Cancer: A Meta-Analysis.

Background. Abdominoperineal resection (APR) has been the standard surgery for ultra-low rectal cancer for a century. In recent years, intersphincteric resection (ISR) has been increasingly used to avoid the permanent colostomy. Up to now, there is no relevant meta-analysis comparing the clinical efficacy of ISR and APR. This meta-analysis aimed to compare the outcomes of these 2 procedures. Methods. A comprehensive search of online databases was performed on PubMed, EMBASE, and the Cochrane Library to obtain comparative studies of ISR and APR. Then the data from studies that met the inclusion criteria were extracted and analyzed. Results. A total of 12 studies covering 2438 patients were included. No significant differences were found between ISR and APR in gender, body mass index, distance from tumor to anal edge, operative time, and blood loss. In addition, hospital stay (weighted mean differences = -2.98 days; 95% confidence interval [CI] = -3.54 to -2.43; P < .00001) and postoperative morbidity (odds ratio [OR] = 0.76; 95% CI = 0.59 to 0.99; P = .04) were significantly lower in ISR group compared with APR group. However, patients who underwent ISR showed lower pathological T-stage (T3T4%, OR = 0.49; 95% CI = 0.28 to 0.86; P = .01) and lymph node metastasis rate (OR = 0.77; 95% CI = 0.59 to 1.01; P = .06) compared with those who underwent APR. Moreover, oncological outcomes were similar between the 2 groups. Conclusion. ISR may provide a safe alternative to APR, with shorter hospital stays, lower postoperative morbidity, and similar oncological outcomes. Well-designed randomized controlled trials are needed to confirm and update the findings of this analysis.

Glove single-port laparoscopy-assisted transanal total mesorectal excision for low rectal cancer: a preliminary report.

PURPOSE: Glove single-port laparoscopy-assisted transanal total mesorectal excision (TaTME) has been successfully carried out in our medical center. The purpose of this study is to evaluate the feasibility of this emerging operation. METHODS: This technique was performed by self-made glove single-port laparoscopic platform to radically resect low rectal cancer. Short-term postoperative results, including complications, length of hospital stay, and follow-up results were collected and analyzed statistically. RESULTS: There are five consecutive patients (three males, two females) who underwent this surgery and included in this study. The mean distance from the tumor to the anal verge was 4.8 cm (range 4.0-6.0). The surgery was completed in all cases, and the rectal tumor was removed successfully without conversion; circumferential margins of all the excised specimens were negative. The mean time of operation was 338.00 min (range 280-400). The average number of lymph node dissection was 12.20. The average postoperative hospital stay was 8.60 days. During the follow-up (14.80 ± 1.92 months), all preventive ileostomies were successfully closed in about 3 months after the surgery, all patients had satisfactory anal function, and no tumor recurrence was found. CONCLUSION: Glove single-port laparoscopy-assisted TaTME has a significant effect in specific patients with low rectal cancer, with rapid recovery and high safety. Prospective randomized studies involving more case counts and long-term follow-up results, especially oncologic outcomes, are needed to validate this technique.

TLR2-dependent and independent pyroptosis in dTHP-1 cells induced by Actinomyces oris MG-1.

In the immune system, the detection of pathogens through various mechanisms triggers immune responses. Several types of specific programmed cell deaths play a role in the inflammatory reaction. This study emphasizes the inflammatory response induced by Actinomycetes. Actinomyces spp. are resident bacteria in human oral plaque and often serve as a bridge for pathogenic bacteria, which lack affinity to the tooth surface, aiding their colonization of the plaque. We aim to investigate the potential role of Actinomyces oris in the early stages of oral diseases from a new perspective. Actinomyces oris MG-1 (A. oris) was chosen for this research. Differentiated THP-1 (dTHP-1) cells were transiently treated with A. oris to model the inflammatory reaction. Cell viability, as well as relative gene and protein expression levels of dTHP-1 cells, were assessed using CCK-8, quantitative real-time polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and Western blot assay. The treatment decreased cell viability and increased the expression of inflammatory genes such as IL-1R1 and NLRP3. It was also observed to significantly enhance the release of IL-1ß/IL-18 into the supernatant. Immunoblot analysis revealed a notable increase in the expression of N-gasdermin D persisting up to 24 h. Conversely, in models pre-treated with TLR2 inhibitors, N-gasdermin D was detectable only 12 h post-treatment and absent at 24 h. These results suggest that Actinomyces oris MG-1 induces pyroptosis in dTHP-1 cells via TLR2, but the process is not solely dependent on TLR2.

Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression.

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

Simultaneous de novo calling and phasing of genetic variants at chromosome-scale using NanoStrand-seq.

The successful accomplishment of the first telomere-to-telomere human genome assembly, T2T-CHM13, marked a milestone in achieving completeness of the human reference genome. The upcoming era of genome study will focus on fully phased diploid genome assembly, with an emphasis on genetic differences between individual haplotypes. Most existing sequencing approaches only achieved localized haplotype phasing and relied on additional pedigree information for further whole-chromosome scale phasing. The short-read-based Strand-seq method is able to directly phase single nucleotide polymorphisms (SNPs) at whole-chromosome scale but falls short when it comes to phasing structural variations (SVs). To shed light on this issue, we developed a Nanopore sequencing platform-based Strand-seq approach, which we named NanoStrand-seq. This method allowed for de novo SNP calling with high precision (99.52%) and acheived a superior phasing accuracy (0.02% Hamming error rate) at whole-chromosome scale, a level of performance comparable to Strand-seq for haplotype phasing of the GM12878 genome. Importantly, we demonstrated that NanoStrand-seq can efficiently resolve the MHC locus, a highly polymorphic genomic region. Moreover, NanoStrand-seq enabled independent direct calling and phasing of deletions and insertions at whole-chromosome level; when applied to long genomic regions of SNP homozygosity, it outperformed the strategy that combined Strand-seq with bulk long-read sequencing. Finally, we showed that, like Strand-seq, NanoStrand-seq was also applicable to primary cultured cells. Together, here we provided a novel methodology that enabled interrogation of a full spectrum of haplotype-resolved SNPs and SVs at whole-chromosome scale, with broad applications for species with diploid or even potentially polypoid genomes.

One-Step Surface-to-Bulk Modification of High-Voltage and Long-Life LiCoO2 Cathode with Concentration Gradient Architecture.

Raising the charging cut-off voltage of layered oxide cathodes can improve their energy density. However, it inevitably introduces instabilities regarding both bulk structure and surface/interface. Herein, exploiting the unique characteristics of high-valence Nb5+ element, a synchronous surface-to-bulk-modified LiCoO2 featuring Li3 NbO4 surface coating layer, Nb-doped bulk, and the desired concentration gradient architecture through one-step calcination is achieved. Such a multifunctional structure facilitates the construction of high-quality cathode/electrolyte interface, enhances Li+ diffusion, and restrains lattice-O loss, Co migration, and associated layer-to-spinel phase distortion. Therefore, a stable operation of Nb-modified LiCoO2 half-cell is achieved at 4.6 V (90.9% capacity retention after 200 cycles). Long-life 250 Wh kg-1 and 4.7 V-class 550 Wh kg-1 pouch cells assembled with graphite and thin Li anodes are harvested (both beyond 87% after 1600 and 200 cycles). This multifunctional one-step modification strategy establishes a technological paradigm to pave the way for high-energy density and long-life lithium-ion cathode materials.

TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer.

Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway is vital for anti-tumor immunity, but its role in tumor vasculature is unclear. Herein, using preclinical liver cancer models in Cgas/Sting-deficient male mice, we report that the interdependence between tumor cGAS and host STING mediates vascular normalization and anti-tumor immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates tumor cGAS expression and produces cGAMP. Subsequently, cGAMP is transported via LRRC8C channels to activate STING in endothelial cells, enhancing recruitment and transendothelial migration of lymphocytes. In vivo studies in male mice also reveal that administration of vitamin C, a promising anti-cancer agent, stimulates TET2 activity, induces tumor vascular normalization and enhances the efficacy of anti-PD-L1 therapy alone or in combination with IL-2. Our findings elucidate a crosstalk between tumor and vascular endothelial cells in the tumor immune microenvironment, providing strategies to enhance the efficacy of combinational immunotherapy for liver cancer.

Seed and Soil: Consensus Molecular Subgroups (CMS) and Tumor Microenvironment Features Between Primary Lesions and Metastases of Different Organ Sites in Colorectal Cancer.

Purpose: Consensus molecular subtypes (CMS) are mainly used for biological interpretability and clinical stratification of colorectal cancer (CRC) in primary tumors (PT) but few in metastases. The heterogeneity of CMS distribution in metastases and the concordance of CMS between PT and metastases still lack sufficient study. We used CMS to classify CRC metastases and combine it with histopathological analysis to explore differences between PT and distant metastases. Patients and Methods: We obtained gene expression profiles for 942 PT samples from TCGA database (n=376) and GEO database (n=566), as well as 442 metastasis samples from GEO database. Among these, 765 PT samples and 442 metastasis samples were confidently identified with CMS using the "CMS classifier" and enrolled for analysis. Clinicopathological manifestation and CMS classification of CRC metastases were assessed with data from GEO, TCGA, and cBioPortal. Overall, 105 PT-metastasis pairs were extracted from 10 GEO datasets to assess CMS concordance. Tumor microenvironment (TME) features between PT and metastases were analyzed by immune-stromal infiltration with ESTIMATE and xCell algorithms. Finally, TME features were validated with multiplex immunohistochemistry in 27 PT-metastasis pairs we retrospectively collected. Results: Up to 64% of CRC metastases exhibited concordant CMS groups with matched PT, and the TME of metastases was similar to that of PT. For most common distant metastases, liver metastases were predominantly CMS2 and lung and peritoneal metastases were mainly CMS4, highlighting "seed" of tumor cells of different CMS groups had a preference for metastasis to "soil" of specific organs. Compared with PT, cancer-associated fibroblasts (CAF) reduced in liver metastases, CD4+T cells and M2-like macrophages increased in lung metastases, and M2-like macrophages and CAF increased in peritoneal metastases. Conclusion: Our findings underscore the importance of CMS-guided specific organ monitoring and treatment post-primary tumor surgery for patients. Differences in immune-stromal infiltration among different metastases provide targeted therapeutic opportunities for metastatic CRC.

Copper in hepatocellular carcinoma： A double-edged sword with therapeutic potentials.

Copper is a necessary cofactor vital for maintaining biological functions, as well as participating in the development of cancer. A plethora of studies have demonstrated that copper is a double-edged sword, presenting both benefits and detriments to tumors. The liver is a metabolically active organ, and an imbalance of copper homeostasis can result in deleterious consequences to the liver. Hepatocellular carcinoma (HCC), the most common primary liver cancer, is a highly aggressive malignancy with limited viable therapeutic options. As research advances, the focus has shifted towards the relationships between copper and HCC. Innovatively, cuproplasia and cuproptosis have been proposed to depict copper-related cellular growth and death, providing new insights for HCC treatment. By summarizing the constantly elucidated molecular connections, this review discusses the mechanisms of copper in the pathogenesis, progression, and potential therapeutics of HCC. Additionally, we aim to tentatively provide a theoretical foundation and gospel for HCC patients.

Simple transanal total mesorectal resection versus laparoscopic transabdominal total mesorectal resection for the treatment of low rectal cancer: a single-center retrospective case-control study.

Aim: To evaluate the efficacy and safety of simple TaTNE in the treatment of low rectal cancer compared with laparoscopic transabdominal TME. Methods: We collected patients with low rectal cancer admitted to our hospital between January 2019 and November 2021 who received simple TaTME or laparoscopic transabdominal TME. The main outcome was the integrity of the TME specimen. Secondary outcomes were the number of lymph nodes dissected, intraoperative blood loss, operative time, surgical conversion rate, Specimen resection length, circumferential margin (CRM), and distal resection margin (DRM), complication rate. In addition, the Wexner score and LARS score of fecal incontinence were performed in postoperative follow-up. Results: Pathological tissues were successfully resected in all patients. all circumferential margins of the specimen were negative. Specimen resection length was not statistically significant (9.94 ± 2.85 vs. 8.90 ± 2.49, P > 0.05). The incidence of postoperative complications in group A (n = 0) was significantly lower than that in group B (n = 3) (P > 0.05). There was no significant difference in operation time between group A and group B (296 ± 60.36 vs. 305 ± 58.28, P > 0.05). Among the patients with follow-up time less than 1 year, there was no significant difference in Wexner score and LARS score between group A and group B (P > 0.05). However, in patients who were followed up for more than 1 year, the Wexner score in group A (9.25 ± 2.73) was significantly lower than that in group B (17.36 ± 10.95) and was statistically significant (P < 0.05). Conclusion: For radical resection of low rectal cancer, Simple TaTME resection may be as safe and effective as laparoscopic transabdominal TME, and the long-term prognosis may be better.

Virtual biopsy using CT radiomics for evaluation of disagreement in pathology between endoscopic biopsy and postoperative specimens in patients with gastric cancer: a dual-energy CT generalizability study.

PURPOSE: To develop a noninvasive radiomics-based nomogram for identification of disagreement in pathology between endoscopic biopsy and postoperative specimens in gastric cancer (GC). MATERIALS AND METHODS: This observational study recruited 181 GC patients who underwent pre-treatment computed tomography (CT) and divided them into a training set (n = 112, single-energy CT, SECT), a test set (n = 29, single-energy CT, SECT) and a validation cohort (n = 40, dual-energy CT, DECT). Radiomics signatures (RS) based on five machine learning algorithms were constructed from the venous-phase CT images. AUC and DeLong test were used to evaluate and compare the performance of the RS. We assessed the dual-energy generalization ability of the best RS. An individualized nomogram combined the best RS and clinical variables was developed, and its discrimination, calibration, and clinical usefulness were determined. RESULTS: RS obtained with support vector machine (SVM) showed promising predictive capability with AUC of 0.91 and 0.83 in the training and test sets, respectively. The AUC of the best RS in the DECT validation cohort (AUC, 0.71) was significantly lower than that of the training set (Delong test, p = 0.035). The clinical-radiomic nomogram accurately predicted pathologic disagreement in the training and test sets, fitting well in the calibration curves. Decision curve analysis confirmed the clinical usefulness of the nomogram. CONCLUSION: CT-based radiomics nomogram showed potential as a clinical aid for predicting pathologic disagreement status between biopsy samples and resected specimens in GC. When practicability and stability are considered, the SECT-based radiomics model is not recommended for DECT generalization. CRITICAL RELEVANCE STATEMENT: Radiomics can identify disagreement in pathology between endoscopic biopsy and postoperative specimen.

WD repeat protein 54-mediator of ErbB2-driven cell motility 1 axis promotes bladder cancer tumorigenesis and metastasis and impairs chemosensitivity.

One of the most abundant protein-protein interaction domains in the human proteome is the WD40 repeat (WDR) domain. A Gene Expression Omnibus dataset revealed 37 differentially expressed WDR domain genes in bladder cancer (BC). WD repeat domain 54 (WDR54), an upregulated WDR domain gene, was selected for further investigation. Sixty pairs of frozen BC tumor and non-malignant bladder tissues and 83 paraffin-embedded BC tissue specimens were obtained. Loss-/gain-of-function experiments were carried out using BC and xenograft tumor models. WDR54 was overexpressed in BC cells, and its high expression was linked to tumor stage and lymph node metastases in patients. WDR54 contributed to the tumorigenesis and metastasis of BC and impaired its chemosensitivity. WDR54 prevented the degradation and ubiquitination of the mediator of ErbB2-driven cell motility 1 (MEMO1). WDR54 also promoted the interaction between MEMO1 and insulin receptor substrate 1 (IRS1) and activated the IRS1/AKT/ß-catenin pathway in BC cells. Particularly, WDR54 depended on MEMO1 to exert its biological functions. Our study demonstrated the relevance of WDR54 in BC and provides insight into the molecular mechanism underlying BC.

Single-cell and spatial transcriptome analysis reveals the cellular heterogeneity of liver metastatic colorectal cancer.

In this study, we comprehensively charted the cellular landscape of colorectal cancer (CRC) and well-matched liver metastatic CRC using single-cell and spatial transcriptome RNA sequencing. We generated 41,892 CD45- nonimmune cells and 196,473 CD45+ immune cells from 27 samples of six CRC patients, and found that CD8_CXCL13 and CD4_CXCL13 subsets increased significantly in liver metastatic samples that exhibited high proliferation ability and tumor-activating characterization, contributing to better prognosis of patients. Distinct fibroblast profiles were observed in primary and liver metastatic tumors. F3+ fibroblasts enriched in primary tumors contributed to worse overall survival by expressing protumor factors. However, MCAM+ fibroblasts enriched in liver metastatic tumors might promote generation of CD8_CXCL13 cells through Notch signaling. In summary, we extensively analyzed the transcriptional differences of cell atlas between primary and liver metastatic tumors of CRC by single-cell and spatial transcriptome RNA sequencing, providing different dimensions of the development of liver metastasis in CRC.

Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation.

Adenosine 5'-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl-coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.

Similarity-Based Method with Multiple-Feature Sampling for Predicting Drug Side Effects.

Drugs can treat different diseases but also bring side effects. Undetected and unaccepted side effects for approved drugs can greatly harm the human body and bring huge risks for pharmaceutical companies. Traditional experimental methods used to determine the side effects have several drawbacks, such as low efficiency and high cost. One alternative to achieve this purpose is to design computational methods. Previous studies modeled a binary classification problem by pairing drugs and side effects; however, their classifiers can only extract one feature from each type of drug association. The present work proposed a novel multiple-feature sampling scheme that can extract several features from one type of drug association. Thirteen classification algorithms were employed to construct classifiers with features yielded by such scheme. Their performance was greatly improved compared with that of the classifiers that use the features yielded by the original scheme. Best performance was observed for the classifier based on random forest with MCC of 0.8661, AUROC of 0.969, and AUPR of 0.977. Finally, one key parameter in the multiple-feature sampling scheme was analyzed.