Cancer-derived exosomal lncRNA SNHG3 promotes the metastasis of colorectal cancer through hnRNPC-mediating RNA stability of ß-catenin.

Metastasis is the leading cause of death in colorectal cancer (CRC) patients. By mediating intercellular communication, exosomes exhibit considerable value in regulating tumor metastasis. Long non-coding RNAs (lncRNAs) are abundant in exosomes and participate in regulating tumor progression. However, it is poorly understood how the cancer-secreted exosomal lncRNAs affect CRC proliferation and metastasis. Here, by analyzing the public databases we identified a lncRNA SNHG3 and demonstrated that SNHG3 was delivered through CRC cells-derived exosomes to promote metastasis in CRC. Mechanistically, exosomal SNHG3 was internalized by CRC cells and afterward upregulated the expression of ß-catenin by facilitating the intranuclear transport of hnRNPC. Consequently, the RNA stability of ß-catenin was enhanced which led to the activation of EMT and metastasis of CRC cells. Our findings expand the oncogenic mechanisms of exosomal SNHG3 and identify it as a diagnostic marker for CRC.

New insights into the interactions between the gut microbiota and the inflammatory response to ulcerative colitis in a mouse model of dextran sodium sulfate and possible mechanisms of action for treatment with PE&AFWE.

BACKGROUND: Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation. Intestinal innate immunity, including innate immune cells, defends against pathogens and excessive entry of gut microbiota, while preserving immune tolerance to resident intestinal microbiota, and may be characterized by its capacity to produce a rapid and nonspecific reaction. The association between microbiota dysbiosis and the pathogenesis of IBD is complex and dynamic. When the intestinal ecosystem is in dysbiosis, the reduced abundance and diversity of intestinal gut microbiota make the host more vulnerable to the attack of exogenous and endogenous pathogenic gut microbiota. The aim of our study was to comprehensively assess the relationship between microbial populations within UC, the signaling pathways of pathogenic gut microbe therein and the inflammatory response, as well as to understand the effects of using PE&AFWE (poppy extract [Papaver nudicaule L.] and Artemisia frigida Willd. extract) on UC modulation. METHODS: A UC mouse model was established by inducing SPF-grade C57BL/6 mice using dextrose sodium sulfate (DSS). Based on metagenomic sequencing to characterize the gut microbiome, the relationship between gut microbiota dysbiosis and gut microbiota was further studied using random forest and Bayesian network analysis methods, as well as histopathological analysis. RESULTS: (1) We found that the 5 gut microbiota with the highest relative abundance of inflammatory bowel disease UC model gut microbiota were consistent with the top 5 ranked natural bacteria. There were three types of abundance changes in the model groups: increases (Chlamydiae/Proteobacteria and Deferribacteres), decreases (Firmicutes), and no significant changes (Bacteroidetes). The UC model group was significantly different from the control group, with 1308 differentially expressed species with abundance changes greater than or equal to 2-fold. (2) The proportion of the fecal flora in the UC group decreased by 37.5% in the Firmicutes and increased by 14.29% in the proportion of Proteobacteria compared to the control group before treatment. (3) The significantly enriched and increased signaling pathways screened were the 'arachidonic acid metabolic pathway' and the 'phagosomal pathway', which both showed a decreasing trend after drug administration. (4) Based on the causal relationship between different OTUs and the UC model/PE&AFWE administration, screening for directly relevant OTU networks, the UC group was found to directly affect OTU69, followed by a cascade of effects on OTU12, OTU121, OTU93, and OTU7, which may be the pathway of action that initiated the pathological changes in normal mice. (5) We identified a causal relationship between common differentially expressed OTUs and PE&AFWE and UC in the pre- and post-PE&AFWE-treated groups. Thereby, we learned that PE&AFWE can directly affect OTU90, after which it inhibits UC, inhibiting the activity of arachidonic acid metabolic pathway by affecting OTU118, which in turn inhibits the colonization of gut microbiota by OTU93 and OTU7. (6) Histopathological observation and scoring (HS) of the colon showed that there was a significant difference between the model group and the control group (p < 0.001), and that there was a significant recovery in both the sulfasalazine (SASP)and the PE&AFWE groups after the administration of the drug (p < 0.0001). CONCLUSION: We demonstrated causal effects and inflammatory metabolic pathways in gut microbiota dysbiosis and IBD, with five opportunistic pathogens directly contributing to IBD. PE&AFWE reduced the abundance of proteobacteria in the gut microbiota, and histopathology showed significant improvement.

Comprehensive multi-omics analysis and experimental verification reveal PFDN5 is a novel prognostic and therapeutic biomarker for gastric cancer.

Prefoldin Subunit 5 (PFDN5) plays a critical role as a member of the prefoldins (PFDNs) in maintaining a finely tuned equilibrium between protein production and degradation. However, there has been no comprehensive analysis specifically focused on PFDN5 thus far. Here, a comprehensive multi-omics (transcriptomics, genomics, and proteomics) analysis, systematic molecular biology experiments (in vitro and in vivo), transcriptome sequencing and PCR Array were performed for identifying the value of PFDN5 in pan-cancer, especially in Gastric Cancer (GC). We found PFDN5 had the potential to serve as a prognostic and therapeutic biomarker in GC. And PFDN5 could promote the proliferation of GC cells, primarily by affecting the cell cycle, cell death and immune process etc. These findings provide novel insights into the molecular mechanisms and precise treatments of in GC.

GC-CDSS: Personalized gastric cancer treatment recommendations system based on knowledge graph.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in the world, posing a serious threat to human health. Currently, gastric cancer treatment strategies emphasize a multidisciplinary team (MDT) consultation approach. However, there are numerous treatment guidelines and insights from clinical trials. The application of AI-based Clinical Decision Support System (CDSS) in tumor diagnosis and screening is increasing rapidly. OBJECTIVE: The purpose of this study is to (1) summarize the treatment decision process for GC according to the treatment guidelines in China, and then create a knowledge graph (KG) for GC, (2) based on aforementioned KG, built a CDSS and conducted an initial feasibility evaluation for the current system. METHODS: Firstly, we summarized the decision-making process for treatment of GC. Then, we extracted relevant decision nodes and relationships and utilized Neo4j to create the KG. After obtaining the initial node features for building the graph embedding model, graph embedding algorithm, such as Node2Vec and GraphSAGE, were used to construct the GC-CDSS. At last, a retrospective cohort study was used to compare the consistency between GC-CDSS and MDT in treatment decision making. RESULTS: In current study, we introduce a GC-CDSS, which is constructed based on Chinese GC treatment guidelines knowledge graph (KG). In the KG, we define four types of nodes and four types of relationships, and it comprise a total of 207 nodes and 300 relationships. Regarding GC-CDSS, the system is capable of providing dynamic and personalized diagnostic and treatment recommendations based on the patient's condition. Furthermore, a retrospective cohort study is conducted to compare GC-CDSS recommendations with those of the MDT group, the overall consistency rate of treatment recommendations between the auxiliary decision system and MDT team is 92.96%. CONCLUSIONS: We construct a GC treatment support system, GC-CDSS, based on KG. The GC-CDSS may help oncologists make treatment decisions more efficient and promote standardization in primary healthcare settings.

ISL1 and POU4F1 Directly Interact to Regulate the Differentiation and Survival of Inner Ear Sensory Neurons.

The inner ear sensory neurons play a pivotal role in auditory processing and balance control. Though significant progresses have been made, the underlying mechanisms controlling the differentiation and survival of the inner ear sensory neurons remain largely unknown. During development, ISL1 and POU4F transcription factors are co-expressed and are required for terminal differentiation, pathfinding, axon outgrowth and the survival of neurons in the central and peripheral nervous systems. However, little is understood about their functional relationship and regulatory mechanism in neural development. Here, we have knocked out Isl1 or Pou4f1 or both in mice of both sexes. In the absence of Isl1, the differentiation of cochleovestibular ganglion (CVG) neurons is disturbed and with that Isl1-deficient CVG neurons display defects in migration and axon pathfinding. Compound deletion of Isl1 and Pou4f1 causes a delay in CVG differentiation and results in a more severe CVG defect with a loss of nearly all of spiral ganglion neurons (SGNs). Moreover, ISL1 and POU4F1 interact directly in developing CVG neurons and act cooperatively as well as independently in regulating the expression of unique sets of CVG-specific genes crucial for CVG development and survival by binding to the cis-regulatory elements including the promoters of Fgf10, Pou4f2, and Epha5 and enhancers of Eya1 and Ntng2 These findings demonstrate that Isl1 and Pou4f1 are indispensable for CVG development and maintenance by acting epistatically to regulate genes essential for CVG development.

Surgical treatment for right-side aortic arch concomitant with Kommerell's diverticulum: techniques selection and follow-up results.

BACKGROUND: Right-side aortic arch concomitant with Kommerell's diverticulum (KD) is a rare and complex ailment, and there is no consensus on the optimal strategy to deal with this congenital anomaly. We retrospectively analyzed and summary of the cases treated in our center with individual treatment methods for different situations. METHODS: Between September 2018 and December 2021, 10 patients experienced surgical therapy at our institution who presented with a Kommerell's diverticulum arising from an aberrant subclavian artery from the right-side aortic arch. Four main surgical techniques were applied to those patients: 1. total arch replacement with frozen elephant trunk implantation (n = 2); 2. hybrid procedure combining open arch repair and endovascular intervention (n = 1); 3. total endovascular repair using thoracic endovascular aortic repair (TEVAR) with or without left subclavian artery (LSCA) revascularization (n = 6); 4. direct repair underwent endoaneurysmorrhaphy. Clinical characteristics and outcomes were collected. RESULTS: The mean age of these 10 patients was 56.5 years (range 29-79 years) and only 1 woman. The pathology includes aortic dissection (n = 6) and aneurysm (n = 4). The mean diverticulum size was 41.4 [24.2-56.8] mm. There were no in-hospital deaths, and the median hospital stay was 22 [15-43] days. During the follow-up period (21.4 months, 1-44 months), one died of an unknown cause and one died of esophageal fistula. Two patients underwent second-stage endovascular intervention for distal lesion. And none of the patients had endoleak during the follow-up period. CONCLUSIONS: Each of the procedures we have mentioned here has its advantages and disadvantages; individualized treatment should meet the appropriate indications. A single-branched stent graft is feasible and effective in the treatment of aortic disease combined with Kommerell's diverticulum.

Stereocontrolled Synthesis of α-3-Deoxy-d-manno-oct-2-ulosonic Acid (α-Kdo) Glycosides Using C3-p-Tolylthio-Substituted Kdo Donors: Access to Highly Branched Kdo Oligosaccharides.

3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is an eight-carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α-Kdo glycosides with a C3-p-tolylthio-substituted Kdo phosphite donor. The presence of the p-tolylthio group enhanced the reactivity, suppressed the formation of elimination by-products (2,3-enes), and provided complete α-stereocontrol. A variety of Kdo α-glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p-tolylthio group can be efficiently removed by free-radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one-pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5-branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8-branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.

Effect of rosin based quaternary ammonium salt on mechanical, hydrophily, antibacterial of cornstarch/polydopamine film for food packaging.

Food packaging made of biobased materials is environmentally friendly, among which starch film is a type of biobased packaging with great development value. Some existing studies have attempted to add polydopamine (PDA) to enhance cross-linking, but there are still problems such as weakness and hydrophilicity, which greatly limit its application. Therefore, this study synthesized rosin based quaternary ammonium salt-modified cornstarch (ST-B), which was used to replace part of unmodified cornstarch (ST). In the prepared ST/PDA0.5/ST-B5 film, the introduction of a rigid rosin structure increased the stress and water contact angle of the ST/PDA0.5 film by 62 % and 26 %, respectively, while reducing its wettability and WVP; thus, further enhancing its antioxidant activity. Due to the antibacterial ability of rosin quaternary ammonium cations, the packaging film containing 7 wt% ST-B can kill >94.6 % of S. aureus and 99.9 % of E. coli, and can also extend the shelf life of strawberries. In addition, it is proven that the packaging film has good biocompatibility and high safety within cytotoxicity tests and 30-day gavage tests in mice. Therefore, the prepared ST/PDA/ST-B film has more potential for application in food preservation.

PuRenDan alleviates type 2 diabetes mellitus symptoms by modulating the gut microbiota and its metabolites.

ETHNOPHARMACOLOGICAL RELEVANCE: PuRenDan (PRD) is a traditional Chinese medicine formula comprising five herbs that have been traditionally used to treat type 2 diabetes mellitus (T2DM). While PRD has been shown to be effective in treating T2DM in clinical and animal studies, the mechanisms by which it works on the gut microbiome and metabolites related to T2DM are not well understood. AIM OF THE STUDY: The objective of this study was to partially elucidate the mechanism of PRD in treating T2DM through analyses of the gut microbiota metagenome and metabolome. MATERIALS AND METHODS: Sprague-Dawley rats were fed high-fat diets (HFDs) and injected with low-dose streptozotocin (STZ) to replicate T2DM models. Then the therapeutic effects of PRD were evaluated by measuring clinical markers such as blood glucose, insulin resistance (IR), lipid metabolism biomarkers (total cholesterol, low-density lipoprotein, non-esterified fatty acids, and triglycerides), and inflammatory factors (tumor necrosis factor alpha, interleukin-6 [IL-6], interferon gamma, and IL-1ß). Colon contents were collected, and metagenomics, combined with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry metabolic profiling, was performed to evaluate the effects of T2DM and PRD on gut microbiota and its metabolites in rats. Spearman analysis was used to calculate the correlation coefficient among different microbiota, clinical indices, and metabolites. RESULTS: PRD exhibited significant improvement in blood glucose and IR, and reduced serum levels of lipid metabolism biomarkers and inflammatory factors. Moreover, the diversity and abundance of gut microbiota undergo significant changes in rats with T2DM that PRD was able to reverse. The gut microbiota associated with T2DM including Rickettsiaceae bacterium 4572_127, Psychrobacter pasteurii, Parabacteroides sp. CAG409, and Paludibacter propionicigenes were identified. The gut microbiota most closely related to PRD were Prevotella sp. 10(H), Parabacteroides sp. SN4, Flavobacteriales bacterium, Bacteroides massiliensis, Alistipes indistinctus, and Ruminococcus flavefaciens. Additionally, PRD regulated the levels of gut microbiota metabolites including pantothenic acid, 1-Methylhistamine, and 1-Methylhistidine; these affected metabolites were involved in pantothenate and coenzyme A biosynthesis, histidine metabolism, and secondary bile acid biosynthesis. Correlation analysis illustrated a close relationship among gut microbiota, its metabolites, and T2DM-related indexes. CONCLUSION: Our study provides insights into the gut microbiota and its metabolites of PRD therapy for T2DM. It clarifies the role of gut microbiota and the metabolites in the pathogenesis of T2DM, highlighting the potential of PRD for the treatment of this disease.

Predicting multiple linear stapler firings in double stapling technique with an MRI-based deep-learning model.

Multiple linear stapler firings is a risk factor for anastomotic leakage (AL) in laparoscopic low anterior resection (LAR) using double stapling technique (DST) anastomosis. In this study, our objective was to establish the risk factors for ≥ 3 linear stapler firings, and to create and validate a predictive model for ≥ 3 linear stapler firings in laparoscopic LAR using DST anastomosis. We retrospectively enrolled 328 mid-low rectal cancer patients undergoing laparoscopic LAR using DST anastomosis. With a split ratio of 4:1, patients were randomly divided into 2 sets: the training set (n = 260) and the testing set (n = 68). A clinical predictive model of ≥ 3 linear stapler firings was constructed by binary logistic regression. Based on three-dimensional convolutional networks, we built an image model using only magnetic resonance (MR) images segmented by Mask region-based convolutional neural network, and an integrated model based on both MR images and clinical variables. Area under the curve (AUC), sensitivity, specificity, accuracy, positive predictive value (PPV), and Youden index were calculated for each model. And the three models were validated by an independent cohort of 128 patients. There were 17.7% (58/328) patients received ≥ 3 linear stapler firings. Tumor size ≥ 5 cm (odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.15-5.60, p = 0.021) and preoperative carcinoma embryonic antigen (CEA) level > 5 ng/mL [OR = 2.20, 95% CI = 1.20-4.04, p = 0.011] were independent risk factors associated with ≥ 3 linear stapler firings. The integrated model (AUC = 0.88, accuracy = 94.1%) performed better on predicting ≥ 3 linear stapler firings than the clinical model (AUC = 0.72, accuracy = 86.7%) and the image model (AUC = 0.81, accuracy = 91.2%). Similarly, in the validation set, the integrated model (AUC = 0.84, accuracy = 93.8%) performed better than the clinical model (AUC = 0.65, accuracy = 65.6%) and the image model (AUC = 0.75, accuracy = 92.1%). Our deep-learning model based on pelvic MR can help predict the high-risk population with ≥ 3 linear stapler firings in laparoscopic LAR using DST anastomosis. This model might assist in determining preoperatively the anastomotic technique for mid-low rectal cancer patients.

"Drum Tower Hospital" strategy for acute type A aortic dissection with coma.

OVERVIEW: Acute type A aortic dissection (ATAAD) with persistent coma is a life-threatening condition associated with high mortality and poor neurological outcomes. The optimal timing for surgical intervention in these patients remains uncertain, and many patients are not eligible for surgery due to their poor prognosis. DESCRIPTION: In this case, a 53-year-old man with hypertension presented to the emergency department in a coma that had lasted for 9 hours. The patient was diagnosed with ATAAD and underwent the "Drum Tower Hospital" strategy, which involved preoperative assessments, including computed tomography angiography (CTA) and quantitative electroencephalogram (qEEG) monitoring. Surgical interventions, such as emergency stenting and aortic replacement, were performed to restore blood flow and repair the aorta. Postoperative monitoring, including qEEG, showed improvements in brain function. Despite the patient experiencing hemiplegia and a neurological deficit, the "Drum Tower Hospital" strategy, guided by comprehensive brain assessments, showed promise in managing ATAAD with coma. However, further research is needed to establish effective treatment strategies for these patients. Overall, ATAAD with persistent coma is a critical condition with limited treatment options. The "Drum Tower Hospital" strategy, supported by multimodal brain assessment, offers a potential approach to improve outcomes in these patients.

Exploring the relationship between lactate metabolism and immunological function in colorectal cancer through genes identification and analysis.

Introduction: Metabolic dysregulation is a widely acknowledged contributor for the development and tumorigenesis of colorectal cancer (CRC), highlighting the need for reliable prognostic biomarkers in this malignancy. Methods: Herein, we identified key genes relevant to CRC metabolism through a comprehensive analysis of lactate metabolism-related genes from GSEA MsigDB, employing univariate Cox regression analysis and random forest algorithms. Clinical prognostic analysis was performed following identification of three key genes, and consistent clustering enabled the classification of public datasets into three patterns with significant prognostic differences. The molecular pathways and tumor microenvironment (TME) of these patterns were then investigated through correlation analyses. Quantitative PCR was employed to quantify the mRNA expression levels of the three pivotal genes in CRC tissue. Single-cell RNA sequencing data and fluorescent multiplex immunohistochemistry were utilized to analyze relevant T cells and validate the correlation between key genes and CD4+ T cells. Results: Our analysis revealed that MPC1, COQ2, and ADAMTS13 significantly stratify the cohort into three patterns with distinct prognoses. Additionally, the immune infiltration and molecular pathways were significantly different for each pattern. Among the key genes, MPC1 and COQ2 were positively associated with good prognosis, whereas ADAMTS13 was negatively associated with good prognosis. Single-cell RNA sequencing (scRNA-seq) data illustrated that the relationship between three key genes and T cells, which was further confirmed by the results of fluorescent multiplex immunohistochemistry demonstrating a positive correlation between MPC1 and COQ2 with CD4+ T cells and a negative correlation between ADAMTS13 and CD4+ T cells. Discussion: These findings suggest that the three key lactate metabolism genes, MPC1, COQ2, and ADAMTS13, may serve as effective prognostic biomarkers and support the link between lactate metabolism and the immune microenvironment in CRC.

Inducible Rbpms-CreERT2 Mouse Line for Studying Gene Function in Retinal Ganglion Cell Physiology and Disease.

Retinal ganglion cells (RGCs) are the sole output neurons conveying visual stimuli from the retina to the brain, and dysfunction or loss of RGCs is the primary determinant of visual loss in traumatic and degenerative ocular conditions. Currently, there is a lack of RGC-specific Cre mouse lines that serve as invaluable tools for manipulating genes in RGCs and studying the genetic basis of RGC diseases. The RNA-binding protein with multiple splicing (RBPMS) is identified as the specific marker of all RGCs. Here, we report the generation and characterization of a knock-in mouse line in which a P2A-CreERT2 coding sequence is fused in-frame to the C-terminus of endogenous RBPMS, allowing for the co-expression of RBPMS and CreERT2. The inducible Rbpms-CreERT2 mice exhibited a high recombination efficiency in activating the expression of the tdTomato reporter gene in nearly all adult RGCs as well as in differentiated RGCs starting at E13.5. Additionally, both heterozygous and homozygous Rbpms-CreERT2 knock-in mice showed no detectable defect in the retinal structure, visual function, and transcriptome. Together, these results demonstrated that the Rbpms-CreERT2 knock-in mouse can serve as a powerful and highly desired genetic tool for lineage tracing, genetic manipulation, retinal physiology study, and ocular disease modeling in RGCs.

Biodegradable FePS3 nanoplatform for efficient treatment of osteosarcoma by combination of gene and NIR-II photothermal therapy.

As a common tumor with high incidence, osteosarcoma possesses extremely poor prognosis and high mortality. Improving the survival of osteosarcoma patients is still a great challenge due to the precipice of advancement in treatment. In this study, a combination strategy of gene therapy and photothermal therapy (PTT) is developed for efficient treatment of osteosarcoma. Two-dimensional (2D) FePS3 nanosheets are synthesized and functionalized by poly-L-lysine-PEG-folic acid (PPF) to fabricate a multifunctional nanoplatform (FePS@PPF) for further loading microRNAs inhibitor, miR-19a inhibitor (anti-miR-19a). The photothermal conversion efficiency of FePS@PPF is up to 47.1% under irradiation by 1064 nm laser. In vitro study shows that anti-miR-19a can be efficiently internalized into osteosarcoma cells through the protection and delivery of FePS@PPF nanaocarrier, which induces up-regulation of PTEN protein and down-regulation p-AKT protein. After intravenous injection, the FePS@PPF nanoplatform specifically accumulates to tumor site of osteosarcoma-bearing mice. The in vitro and in vivo investigations reveal that the combined PTT-gene therapy displays most significant tumor ablation compared with monotherapy. More importantly, the good biodegradability promotes FePS@PPF to be cleared from body avoiding potential toxicity of long-term retention. Our work not only develops a combined strategy of NIR-II PTT and gene therapy mediated by anti-miR-19a/FePS@PPF but also provides insights into the design and applications of other nanotherapeutic platforms.

Impact of Cuproptosis-related markers on clinical status, tumor immune microenvironment and immunotherapy in colorectal cancer: A multi-omic analysis.

Background: Cuproptosis, a novel identified cell death form induced by copper, is characterized by aggregation of lipoylated mitochondrial enzymes and the destabilization of Fe-S cluster proteins. However, the function and potential clinical value of cuproptosis and cuproptosis-related biomarkers in colorectal cancer (CRC) remain largely unknown. Methods: A comprehensive multi-omics (transcriptomics, genomics, and single-cell transcriptome) analysis was performed for identifying the influence of 16 cuproptosis-related markers on clinical status, molecular functions and tumor microenvironment (TME) in CRC. A novel cuproptosis-related scoring system (CuproScore) based on cuproptosis-related markers was also constructed to predict the prognosis of CRC individuals, TME and the response to immunotherapy. In addition, our transcriptome cohort of 15 paired CRC tissue, tissue-array, and various assays in 4 kinds of CRC cell lines in vitro were applied for verification. Results: Cuproptosis-related markers were closely associated with both clinical prognosis and molecular functions. And the cuproptosis-related molecular phenotypes and scoring system (CuproScore) could distinguish and predict the prognosis of CRC patients, TME, and the response to immunotherapy in both public and our transcriptome cohorts. Besides, the expression, function and clinical significance of these markers were also checked and analyzed in CRC cell lines and CRC tissues in our own cohorts. Conclusions: In conclusion, we indicated that cuproptosis and CPRMs played a significant role in CRC progression and in modeling the TME. Inducing cuproptosis may be a useful tool for tumor therapy in the future.

Polyamine metabolism patterns characterized tumor microenvironment, prognosis, and response to immunotherapy in colorectal cancer.

BACKGROUND: Changes in Polyamine metabolism (PAM) have been shown to establish a suppressive tumor microenvironment (TME) and substantially influence the progression of cancer in the recent studies. However, newly emerging data have still been unable to fully illuminate the specific effects of PAM in human cancers. Here, we analyzed the expression profiles and clinical relevance of PAM genes in colorectal cancer (CRC). METHODS: Based on unsupervised consensus clustering and principal component analysis (PCA) algorithm, we designed a scoring model to evaluate the prognosis of CRC patients and characterize the TME immune profiles, with related independent immunohistochemical validation cohort. Through comparative profiling of cell communities defined by single cell sequencing data, we identified the distinct characteristics of polyamine metabolism in the TME of CRC. RESULTS: Three PAM patterns with distinct prognosis and TME features were recognized from 1224 CRC samples. Moreover, CRC patients could be divided into high- and low-PAMscore subgroups by PCA-based scoring system. High PAMscore subgroup were associated to more advanced stage, higher infiltration level of immunosuppressive cells, and unfavorable prognosis. These results were also validated in CRC samples from other public CRC datasets and our own cohort, which suggested PAM genes were ideal biomarkers for predicting CRC prognosis. Notably, PAMscore also corelated with microsatellite instability-high (MSI-H) status, higher tumor mutational burden (TMB), and increased immune checkpoint gene expression, implying a potential role of PAM genes in regulating response to immunotherapy. To further confirm above results, we demonstrated a high-resolution landscape of TME and cell-cell communication network in different PAM patterns using single cell sequencing data and found that polyamine metabolism affected the communication between cancer cells and several immune cells such as T cells, B cells and myeloid cells. CONCLUSION: In total, our findings highlighted the significance of polyamine metabolism in shaping the TME and predicting the prognosis of CRC patients, providing novel strategies for immunotherapy and the targeting polyamine metabolites.

Exploring the role of pyroptosis in shaping the tumor microenvironment of colorectal cancer by bulk and single-cell RNA sequencing.

BACKGROUND: Emerging studies have shown that pyroptosis plays a non-negligible role in the development and treatment of tumors. However, the mechanism of pyroptosis in colorectal cancer (CRC) remains still unclear. Therefore, this study investigated the role of pyroptosis in CRC. METHODS: A pyroptosis-related risk model was developed using univariate Cox regression and LASSO Cox regression analyses. Based on this model, pyroptosis-related risk scores (PRS) of CRC samples with OS time > 0 from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database were calculated. The abundance of immune cells in CRC tumor microenvironment (TME) was predicted by single-sample gene-set enrichment analysis (ssGSEA). Then, the responses to chemotherapy and immunotherapy were predicted by pRRophetic algorithm, the tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms, respectively. Moreover, the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing dataset (PRISM) were used to explore novel drug treatment strategies of CRC. Finally, we investigated pyroptosis-related genes in the level of single-cell and validated the expression levels of these genes between normal and CRC cell lines by RT-qPCR. RESULTS: Survival analysis showed that CRC samples with low PRS had better overall survival (OS) and progression-free survival (PFS). CRC samples with low PRS had higher immune-related gene expression and immune cell infiltration than those with high PRS. Besides, CRC samples with low PRS were more likely to benefit from 5-fluorouracil based chemotherapy and anti-PD-1 immunotherapy. In novel drug prediction, some compounds such as C6-ceramide and noretynodrel, were inferred as potential drugs for CRC with different PRS. Single-cell analysis revealed pyroptosis-related genes were highly expressed in tumor cells. RT-qPCR also demonstrated different expression levels of these genes between normal and CRC cell lines. CONCLUSIONS: Taken together, this study provides a comprehensive investigation of the role of pyroptosis in CRC at the bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) levels, advances our understanding of CRC characteristics, and guides more effective treatment regimens.

Roles and mechanisms of tumour-infiltrating B cells in human cancer: a new force in immunotherapy.

Immune checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 have emerged as a revolutionary treatment strategy for human cancer patients. However, as the response rate to ICI therapy varies widely among different types of tumours, we are beginning to gain insight into the mechanisms as well as biomarkers of therapeutic response and resistance. Numerous studies have highlighted the dominant role of cytotoxic T cells in determining the treatment response to ICIs. Empowered by recent technical advances, such as single-cell sequencing, tumour-infiltrating B cells have been identified as a key regulator in several solid tumours by affecting tumour progression and the response to ICIs. In the current review, we summarized recent advances regarding the role and underlying mechanisms of B cells in human cancer and therapy. Some studies have shown that B-cell abundance in cancer is positively associated with favourable clinical outcomes, while others have indicated that they are tumour-promoting, implying that the biological function of B cells is a complex landscape. The molecular mechanisms involved multiple aspects of the functions of B cells, including the activation of CD8+ T cells, the secretion of antibodies and cytokines, and the facilitation of the antigen presentation process. In addition, other crucial mechanisms, such as the functions of regulatory B cells (Bregs) and plasma cells, are discussed. Here, by summarizing the advances and dilemmas of recent studies, we depicted the current landscape of B cells in cancers and paved the way for future research in this field.

Self-assembly of guanosine into carbon-based multilayer materials.

We report the utilization of guanosine as a supramolecular precursor that unprecedentedly renders the formation of carbon-based multilayer materials with naturally high-level nitrogen doping. As a proof-of-concept, the porous carbon multilayers after anchoring 0.5 wt% Rh electrocatalysts displayed an excellent hydrogen evolution reaction activity.

Infrapyloric (No. 206) and greater curvature (No. 204) lymph node metastasis in adenocarcinoma located in the right half of the transverse colon (InCLART Study): protocol for a multicentre prospective observational study.

INTRODUCTION: In the case of right-sided transverse colon cancer (RTCC) and hepatic flexure colon cancer (HFCC), there is a potential connection of lymph drainage between mesentery and greater omentum. However, most previous reports have been limited case series with No. 206 and No. 204 lymph node (LN) dissection for RTCC and HFCC. METHODS AND ANALYSIS: The InCLART Study is a prospective observational study aiming to enrol 427 patients with RTCC and HFCC treated at 21 high-volume institutions in China. The prevalence of infrapyloric (No. 206) and greater curvature (No. 204) LN metastasis and short-term outcomes will be investigated in a consecutive series of patients with T2 or deeper invasion RTCC or HFCC, following the principle of complete mesocolic excision with central vascular ligation. Primary endpoints were performed to identify the prevalence of No. 206 and No. 204 LN metastasis. Secondary analyses will be used to estimate prognostic outcomes, intraoperative and postoperative complications, the consistency of preoperative evaluation and postoperative pathological results of LN metastasis. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the Ruijin Hospital Ethics Committee (approval number: 2019-081) and has been or will be approved successively by each participating centre's Research Ethics Board. The findings will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03936530; https://clinicaltrials.gov/ct2/show/NCT03936530).