Identification of KRAS mutation-associated gut microbiota in colorectal cancer and construction of predictive machine learning model.

Gut microbiota has demonstrated an increasingly important role in the onset and development of colorectal cancer (CRC). Nonetheless, the association between gut microbiota and KRAS mutation in CRC remains enigmatic. We conducted 16S rRNA sequencing on stool samples from 94 CRC patients and employed the linear discriminant analysis effect size algorithm to identify distinct gut microbiota between KRAS mutant and KRAS wild-type CRC patients. Transcriptome sequencing data from nine CRC patients were transformed into a matrix of immune infiltrating cells, which was then utilized to explore KRAS mutation-associated biological functions, including Gene Ontology items and Kyoto Encyclopedia of Genes and Genomes pathways. Subsequently, we analyzed the correlations among these KRAS mutation-associated gut microbiota, host immunity, and KRAS mutation-associated biological functions. At last, we developed a predictive random forest (RF) machine learning model to predict the KRAS mutation status in CRC patients, based on the gut microbiota associated with KRAS mutation. We identified a total of 26 differential gut microbiota between both groups. Intriguingly, a significant positive correlation was observed between Bifidobacterium spp. and mast cells, as well as between Bifidobacterium longum and chemokine receptor CX3CR1. Additionally, we also observed a notable negative correlation between Bifidobacterium and GOMF:proteasome binding. The RF model constructed using the KRAS mutation-associated gut microbiota demonstrated qualified efficacy in predicting the KRAS phenotype in CRC. Our study ascertained the presence of 26 KRAS mutation-associated gut microbiota in CRC and speculated that Bifidobacterium may exert an essential role in preventing CRC progression, which appeared to correlate with the upregulation of mast cells and CX3CR1 expression, as well as the downregulation of GOMF:proteasome binding. Furthermore, the RF model constructed on the basis of KRAS mutation-associated gut microbiota exhibited substantial potential in predicting KRAS mutation status in CRC patients.IMPORTANCEGut microbiota has emerged as an essential player in the onset and development of colorectal cancer (CRC). However, the relationship between gut microbiota and KRAS mutation in CRC remains elusive. Our study not only identified a total of 26 gut microbiota associated with KRAS mutation in CRC but also unveiled their significant correlations with tumor-infiltrating immune cells, immune-related genes, and biological pathways (Gene Ontology items and Kyoto Encyclopedia of Genes and Genomes pathways). We speculated that Bifidobacterium may play a crucial role in impeding CRC progression, potentially linked to the upregulation of mast cells and CX3CR1 expression, as well as the downregulation of GOMF:Proteasome binding. Furthermore, based on the KRAS mutation-associated gut microbiota, the RF model exhibited promising potential in the prediction of KRAS mutation status for CRC patients. Overall, the findings of our study offered fresh insights into microbiological research and clinical prediction of KRAS mutation status for CRC patients.

Regulating effects of low salt dry-curing pre-treatment on microbiota, biochemical changes and flavour precursors of grass carp (Ctenopharyngodon idella) fillets during storage at 4 °C.

Low salt dry-curing (LSD), as a healthier pre-treatment for the preservation of fishery products, is a potential technique substitute for excessively salty curing. The regulatory effects of 2 % and 3 % LSD on the quality evolution through an intrinsic correlation between microbiota succession and flavour precursors of refrigerated grass carp fillets were investigated in this study. The results showed that the LSD pre-treatment was effective in promoting proteolysis, free amino acid and fatty acid metabolism with the microbiota succession and quality evolution. Compared with unpre-treated samples, the 3 % LSD pre-treatment effectively extended the shelf life by 10 days within the acceptable quality attributes. Not only did the LSD pre-treatment lead to catalytic microbiota succession and inhibitive spoilage substance production but it also improved the flavour precursors, which are taste-active amino acids and polyunsaturated fatty acids (PUFAs). Moreover, considerable correlations between quality attributes, taste-active amino acids, PUFAs and microbiota were obtained.

Analysis of differences in intestinal flora associated with different BMI status in colorectal cancer patients.

BACKGROUND: Overweight is known to be an important risk factor for colorectal cancer (CRC), and the differences in intestinal flora among CRC patients with different BMI status have not been clearly defined. The purpose of this study was to elucidate the differences in the abundance, composition and biological function of intestinal flora in CRC patients with different BMI status. METHOD: A total of 170 CRC patients were included and grouped according to the BMI data of CRC patients. BMI ≥ 24 kg/m2 was defined as overweight group, and BMI within the range of 18.5-23.9 kg/m2 was defined as normal weight group. Preoperative stool collection of patients in both groups was used for 16S rRNA sequencing. Total RNA was extracted from 17 CRC tumor tissue samples for transcriptome sequencing, and then CIBERSORT algorithm was used to convert the transcriptome data into the relative content matrix of 22 kinds of immune cells, and the correlation between different intestinal flora and immune cells and immune-related genes under different BMI states was analyzed. Finally, we identified BMI-related differential functional pathways and analyzed the correlation between these pathways and differential intestinal flora. RESULT: There was no significant difference in α diversity and ß diversity analysis between overweight group and normal weight group. Partial least square discriminant analysis (PLS-DA) could divide the flora into two different clusters according to BMI stratification. A total of 33 BMI-related differential flora were identified by linear discriminant effect size analysis (LEfSe), among which Actinomyces, Desulfovibrio and Bacteroides were significantly enriched in overweight group. ko00514: Other types of O-glycan biosynthesis are significantly enriched in overweight group. There was a significant positive correlation between Clostridium IV and Macrophages M2 and T cells regulatory (Tregs). There was a significant negative correlation with Dendritic cells activated and T cells CD4 memory activated. CONCLUSIONS: The richness and diversity of intestinal flora of CRC patients may be related to different BMI status, and the enrichment of Actinomyces, Desulphurvibrio and Bacteroides may be related to overweight status of CRC patients. The tumor microenvironment in which BMI-related differential flora resides has different immune landscapes, suggesting that some intestinal flora may affect the biological process of CRC by regulating immune cell infiltration and immune gene expression, but further experiments are needed to confirm this.

Multi-omics and single-cell sequencing analyses reveal the potential significance of circadian pathways in cancer therapy.

BACKGROUND: Circadian rhythm disturbance is an independent risk factor for cancer. However, few studies have been reported on circadian rhythm related genes (CRGs) in cancer, so it is important to further explore the impact of CRGs in pan-cancer. RESEARCH DESIGN AND METHODS: The Cancer Genome Atlas database was used to collect cancer-related data such as copy number variation, single nucleotide variants, methylation, and survival differences. Immunohistochemistry (IHC) was used to verify the expression of circadian rhythm hub genes. The circadian pathway scores (CRS) were calculated using single-sample gene enrichment analysis. TIMER and GEPIA databases were used for immune-cell integration and assessment. Single-cell sequencing data was used to evaluate the abundance of CRS in tumor microenvironment cells. RESULTS: In this study, we found that the expression of circadian pathway varies between tumors. CSNK1E was significantly up-regulated in most tumors and CRY2 was significantly down-regulated in most tumors. The protein interaction network suggested CRY2 as the core gene and IHC verified its significant low expression in KIRC. In addition, CRGs were found to be protective factors in most tumors and have the potential to act as specific immune markers in different tumors. CRS was significantly lower in abundance in most tumors. CRS was significantly associated with overall survival in tumor patients and associated with the expression of many immune cells in the tumor immune microenvironment. CRS is significantly associated with tumor mutational burden and microsatellite instability scores in most tumors and may serve as a potential immunotherapeutic marker. CONCLUSIONS: The circadian rhythm pathway may be a breakthrough point in regulating the tumor microenvironment meanwhile a suitable immunotherapy method in the future.

Identification of HSP90B1 in pan-cancer hallmarks to aid development of a potential therapeutic target.

Heat shock proteins play crucial roles in various biochemical processes, encompassing protein folding and translocation. HSP90B1, a conserved member of the heat shock protein family, growing evidences have demonstrated that it might be closely associated with cancer development. In the present study, we employed multi-omics analyses and cohort validations to explore the dynamic expression of HSP90B1 in pan-cancer and comprehensively evaluate HSP90B1 as a novel biomarker that hold promise for precision cancer diagnostics and therapeutics. The results suggest HSP90B1 was highly expressed in various kinds of tumors, often correlating with a poor prognosis. Notably, methylation of HSP90B1 emerged as a protective factor in several cancer types. In immune infiltration analysis, the expression of HSP90B1 in most tumors showed a negative association with CD8 + T cells. HSP90B1 expression was positively correlated with microsatellite instability and tumor mutational burden. HSP90B1 expression was also discovered to be positively correlated with tumor metabolism, cell cycle-related pathways and the expression of immune checkpoint genes. The expression of HSP90B1 was mainly negatively correlated with immunostimulatory genes and positively correlated with immunosuppressive genes, as well as strongly correlated with chemokines and their receptor genes. In addition, the HSP90B1 inhibitor PU-WS13 demonstrated significant efficacy in suppressing cancer cell proliferation in both leukemic and solid tumor cells, and remarkably reduced the expression of the cancer cell surface immune checkpoint PD-L1. The single-cell RNA sequencing analysis further highlighted that HSP90B1 was significantly higher in tumor cells compared to surrounding cells, revealing a potential target therapeutic window. Taken together, HSP90B1 emerges as a promising avenue for breakthroughs in cancer diagnosis, prognosis and therapy. This study provides a rationale for HSP90B1 targeted cancer diagnosis and therapy in future.

CircRUNX1 drives the malignant phenotypes of lung adenocarcinoma through mediating the miR-5195-3p/HMGB3 network.

BACKGROUND: Circular RNAs (circRNAs) are key factors in the regulation of cancer progression. However, the role of circRUNX1 in lung adenocarcinoma (LUAD) progression is unclear. METHODS: The expression levels of circRUNX1, microRNA (miR)-5195-3p, and high-mobility group protein B3 (HMGB3) were detected by quantitative real-time PCR. Cell proliferation, migration, invasion and apoptosis were analyzed by EdU staining, colony formation assay, transwell assay and flow cytometry. Protein levels were measured using western blot analysis. The interaction between miR-5195-3p and circRUNX1 or HMGB3 was verified by dual-luciferase reporter assay and RIP assay. Animal experiments were performed to investigate the role of circRUNX1 in LUAD tumorigenesis. RESULTS: We found that circRUNX1 was upregulated in LUAD tumor tissues and cells. CircRUNX1 knockdown suppressed LUAD cell proliferation and metastasis, while promoted apoptosis. In terms of mechanism, we found that circRUNX1 could sponge miR-5195-3p, and miR-5195-3p inhibitor abolished the regulation of circRUNX1 knockdown on LUAD cell proliferation, metastasis and apoptosis. In addition, miR-5195-3p could target HMGB3, and HMGB3 overexpression reversed the inhibition effect of miR-5195-3p on LUAD progression. Moreover, circRUNX1 knockdown reduced LUAD tumorigenesis. CONCLUSION: CircRUNX1 facilitated LUAD proliferation and metastasis by regulating the miR-5195-3p/HMGB3 axis, suggesting that it might be a possible therapeutic target for LUAD.

Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting.

BACKGROUND: Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias. METHODS: Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues. RESULTS: The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively. CONCLUSION: Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

Intrauterine transmission of SARS-CoV-2 to and prenatal ultrasound abnormal findings in the fetus of a pregnant woman with mild COVID-19.

BACKGROUND: Whether intrauterine transmission of COVID-19 occurs remains uncertain, and it remains unclear whether the disease affects fetuses. We present a case of intrauterine transmission of SARS-CoV-2 infection and the prenatal ultrasonographic findings of the fetus in a pregnant woman with mild COVID-19. CASE PRESENTATION: A 30-year-old woman was admitted to our hospital for ultrasound examination in January 2023 at 26+ 3 weeks' gestation. Twenty-one days prior, her COVID-19 nucleic acid test was positive, and she had mild symptoms, including fever (38.3 °C), headache, chills, ankle pain and cough. After receiving symptomatic treatment, she fully recovered. Prenatal ultrasound revealed that the placenta was diffusely distributed with punctate echogenic foci, hepatomegaly, and the volume of bilateral lungs decreased significantly, with enhanced echo. In addition, we found that the surface of the fetal brain demonstrated widened gyri with a flattened surface. The prenatal MRI confirmed these fetal abnormalities. Amniotic fluid was tested for SARS-CoV-2, and the sample tested was positive for the virus. After careful consideration, the pregnant woman decided to terminate the pregnancy. CONCLUSION: The intrauterine transmission of COVID-19 is certain. Moreover, the intrauterine transmission of COVID-19 may cause abnormalities in various organs of the fetus.

Identification of colorectal cancer progression-associated intestinal microbiome and predictive signature construction.

OBJECTIVE: The relationship between intestinal microbiome and colorectal cancer (CRC) progression is unclear. This study aims to identify the intestinal microbiome associated with CRC progression and construct predictive labels to support the accurate assessment and treatment of CRC. METHOD: The 192 patients included in the study were divided into stage I-II and stage III-IV CRC patients according to the pathological stages, and preoperative stools were collected from both groups for 16S rDNA sequencing of the intestinal microbiota. Pearson correlation and Spearman correlation coefficient analysis were used to analyze the differential intestinal microbiome and the correlation with tumor microenvironment and to predict the functional pathway. XGBoost model (XGB) and Random Forest model (RF) were used to construct the microbiome-based signature. The total RNA extraction from 17 CRC tumor simples was used for transcriptome sequencing. RESULT: The Simpson index of intestinal microbiome in stage III-IV CRC were significantly lower than those in stage I-II CRC. Proteus, Parabacteroides, Alistipes and Ruminococcus etc. are significantly enriched genus in feces of CRC patients with stage III-IV. ko00514: Other types of O - glycan biosynthesis pathway is relevant with CRC progression. Alistipes indistinctus was positively correlated with mast cells, immune activators IL-6 and IL6R, and GOBP_PROTEIN_FOLDING_IN_ENDOPLASMIC_RETICULUM dominantly. The Random Forest (RF) model and eXtreme Gradient Boosting (XGBoost) model constructed with 42 CRC progression-associated differential bacteria were effective in distinguishing CRC patients between stage I-II and stage III-IV. CONCLUSIONS: The abundance and diversity of intestinal microbiome may increase gradually with the occurrence and progression of CRC. Elevated fetal abundance of Proteus, Parabacteroides, Alistipes and Ruminococcus may contribute to CRC progression. Enhanced synthesis of O - glycans may result in CRC progression. Alistipes indistinctus may play a facilitated role in mast cell maturation by boosting IL-6 production. Alistipes indistinctus may work in the correct folding of endoplasmic reticulum proteins in CRC, reducing ER stress and prompting the survival and deterioration of CRC, which may owe to the enhanced PERK expression and activation of downstream UPR by Alistipes indistinctus. The CRC progression-associated differential intestinal microbiome identified in our study can be served as potential microbial markers for CRC staging prediction.

Identification of intestinal microbiome associated with lymph-vascular invasion in colorectal cancer patients and predictive label construction.

Objective: To identify differences between the composition, abundance, and biological function of the intestinal microbiome of patients with and without lymph-vascular invasion (LVI) colorectal cancer (CRC) and to construct predictive labels to support accurate assessment of LVI in CRC. Method: 134 CRC patients were included, which were divided into two groups according to the presence or absence of LVI, and their intestinal microbiomes were sequenced by 16SrRNA and analyzed for differences. The transcriptome sequencing data of 9 CRC patients were transformed into immune cells abundance matrix by CIBERSORT algorithm, and the correlation among LVI-associated differential intestinal microbiomes, immune cells, immune-related genes and LVI-associated differential GO items and KEGG pathways were analyzed. A random forest (RF) and eXtreme Gradient Boosting (XGB) model were constructed to predict the LVI of CRC patients based on the differential microbiome. Result: There was no significant difference in α-diversity and ß-diversity of intestinal microbiome between CRC patients with and without LVI (P > 0.05). Linear discriminant analysis Effect Size (LEfSe) analysis showed 34 intestinal microbiomes enriched in CRC patients of the LVI group and 5 intestinal microbiomes were significantly enriched in CRC patients of the non-lymph-vascular invasion (NLVI) group. The RF and XGB prediction models constructed with the top 15% of the LVI-associated differential intestinal microbiomes ranked by feature significance had good efficacy. Conclusions: There are 39 intestinal flora with significantly different species abundance between the LVI and NLVI groups. g:Alistipes.s:Alistipes_indistinctus is closely associated with colorectal cancer vascular invasion. LVI-associated differential intestinal flora may be involved in regulating the infiltration of immune cells in CRC and influencing the expression of immune-related genes. LVI-associated differential intestinal flora may influence the process of vascular invasion in CRC through a number of potential biological functions. RF prediction models and XGB prediction models constructed based on microbial markers of gut flora can be used to predict CRC-LVI conditions.

Weighted gene co-expression network analysis identifies the prognosis-related models of left- and right-sided colon cancer.

Left-sided colon cancer (LC) and right-sided colon cancer (RC) are 2 essentially different diseases, and the potential mechanisms regulating them remain unidentified. In this study, we applied weighted gene co-expression network analysis (WGCNA) to confirm a yellow module, mainly enriched in metabolism-related signaling pathways related to LC and RC. Based on the RNA-seq data of colon cancer in The Cancer Genome Atlas (TCGA) and GSE41258 dataset with their corresponding clinical information, a training set (TCGA: LC: n = 171; RC: n = 260) and a validation set (GSE41258: LC: n = 94; RC: n = 77) were divided. Least absolute shrinkage and selection operator (LASSO) penalized COX regression analysis identified 20 prognosis-related genes (PRGs) and helped constructed 2 risk (LC-R and RC-R) models in LC and RC, respectively. The model-based risk scores accurately performed in risk stratification for colon cancer patients. The high-risk group of the LC-R model showed associations with ECM-receptor interaction, focal adhesion, and PI3K-AKT signaling pathway. Interestingly, the low-risk group of the LC-R model showed associations with immune-related signaling pathways like antigen processing and presentation. On the other hand, the high-risk group of the RC-R model showed enrichment for cell adhesion molecules and axon guidance signaling pathways. Furthermore, we identified 20 differentially expressed PRGs between LC and RC. Our findings provide new insights into the difference between LC and RC, and uncover the potential biomarkers for the treatment of LC and RC.

Cuproptosis correlates with immunosuppressive tumor microenvironment based on pan-cancer multiomics and single-cell sequencing analysis.

Recent studies suggest that cuproptosis, a novel mode of cell death, may be associated with the development of cancer. However, no studies are showing its role in tumorigenesis, progression, and prognosis. In the present study, we comprehensively analyzed the expression difference, gene variation and methylation modification of cuproptosis-related genes (CRGs) in pan-cancer. Then, Single sample gene set enrichment analysis (ssGSEA) was used to calculate individual cuproptosis scores (CS). The association of CS with copy number variation, clinical features, immune-related genes, TMB, MSI, and tumor immune dysfunction and exclusion (TIDE) was comprehensively assessed. Single-cell transcriptome sequencing (scRNA-seq) to analyze the activation of cuproptosis in the tumor microenvironment. Immunohistochemistry (IHC) were used to validate the expression of cuproptosis hub-gene. Our study shows that CRGs were significantly expressed in a variety of tumors, and CDKN2A had the highest mutation frequency (49%) in all tumors. A significant increase in the CS was observed in most cancers and were associated with poor prognosis in the majority of tumors. CS was significantly negatively correlated with tumor microenvironment scores in more than 10 tumors and positively correlated with PD-L1 in 11 tumors, suggesting involvement in tumor immune escape. scRNA-seq suggests that CRG scores significantly increased in the cancer cells. This study opens avenues for further research on the role of cuproptosis in the occurrence and development of cancer and the development of targeted therapies based on cuproptosis.

A comprehensive review of the control and utilization of aquatic animal products by autolysis-based processes: Mechanism, process, factors, and application.

Animal aquatic products have high water content, abundant enzyme system and their own diverse microbial flora. These products are severely susceptible to autolysis and degradation after death, resulting in many adverse effects on storage, processing, and transportation. Among them, the endogenous enzyme are the key factor that caused the autolysis and degradation. Autolytic hydrolysis provides an effective way to maximize the use of aquatic by-products and achieve increased protein resources and reduce environmental pollution from by-products. To better acquaintance the autolysis phenomenon and regulation of the autolysis phenomenon. This paper reviews the autolytic mechanism, biochemical changes, influencing factors, and potential applications of animal aquatic products and their by-products to explore autolysis and its effective utilization and regulation. In addition, this study also emphasizes the importance of making full use of aquatic by-products. Furthermore, the research trends and future challenges of autolysis are also discussed. Autolysis can effectively transform aquatic products and by-products into bioactive hydrolysates. The hydrolysates produced by the autolysis of aquatic products and their by-products have attracted attention because of their wide applications in food, healthcare, and animal feed industries. However, the mechanism and regulation (promotion or inhibition) of autolysis should be further studied, and autolysate at the industrial level should be produced to provide high-value-added products for by-product processing and realize the sustainable utilization of resources.

Effect of three culture patterns on quality changes of crayfish meats during partial freezing storage.

The quality changes and main metabolites of rice-crayfish (DT), intensive crayfish (JY), and lotus pond crayfish (OT) under three culture patterns during partial freezing were studied. Compared with the DT and JY groups, the OT samples had higher thiobarbituric acid reactive substances (TBARS), K values and color values. The microstructure of the OT samples deteriorated most obviously during storage, and they had the lowest water-holding capacity and the worst texture. Furthermore, differential metabolites of crayfish under different culture patterns were identified by UHPLC-MS, and the most abundant differential metabolites of the OT groups were found. The main differential metabolites include alcohols polyols and carbonyl compounds; amines; amino acids, peptides, and analogues; carbohydrates and carbohydrate conjugates; fatty acids and conjugates. In conclusion, based on the analysis of existing data, the OT groups were considered to be the most serious deterioration during partial freezing compared with the other two culture patterns.

Case Report: Colon malignant tumor caused by retroperitoneal small round cell undifferentiated sarcoma.

Small round cell undifferentiated sarcoma is a rare and highly invasive group of malignant bone and soft tissue tumors, often associated with a high misdiagnosis rate. The patient in this case was a 34-year-old male who presented with a two-month history of abdominal pain that worsened over the past two weeks. Elevated levels of tumor markers CA19-9 and CA72-4 were observed. Imaging revealed a substantial, well-vascularized mass in the lower left abdomen, located in the posterior abdominal cavity, invading the descending colon and the root of the small mesentery, and infiltrating the serous layer. The lesion was extensively resected without any postoperative complications. Microscopic examination indicated a combination of mucinous adenocarcinoma (approximately 30%) and small round cell undifferentiated sarcoma (approximately 70%). The patient was followed up for six months, and one month after surgery, a recurrence of the tumor was observed in the left paracolonic sulcus area, with metastases to the abdominal wall, peritoneum, and medial iliac muscles. Chemotherapy and targeted therapy were administered, and the patient currently survives with the presence of tumors. Small round cell undifferentiated sarcoma is an uncommon and highly invasive tumor, and clinical surgeons need to raise their awareness and realize to the maximum extent possible that this disease can be described through a multi-modal combination of immunohistochemistry and genetic test to improve diagnostic accuracy and reduce missed diagnoses. Further research in the field of biology is necessary to explore targeted drugs specifically suitable for this disease.

Comprehensive multi-omics analysis of the m7G in pan-cancer from the perspective of predictive, preventive, and personalized medicine.

Background: The N7-methylguanosine modification (m7G) of the 5' cap structure in the mRNA plays a crucial role in gene expression. However, the relation between m7G and tumor immune remains unclear. Hence, we intended to perform a pan-cancer analysis of m7G which can help explore the underlying mechanism and contribute to predictive, preventive, and personalized medicine (PPPM / 3PM). Methods: The gene expression, genetic variation, clinical information, methylation, and digital pathological section from 33 cancer types were downloaded from the TCGA database. Immunohistochemistry (IHC) was used to validate the expression of the m7G regulator genes (m7RGs) hub-gene. The m7G score was calculated by single-sample gene-set enrichment analysis. The association of m7RGs with copy number variation, clinical features, immune-related genes, TMB, MSI, and tumor immune dysfunction and exclusion (TIDE) was comprehensively assessed. CellProfiler was used to extract pathological section characteristics. XGBoost and random forest were used to construct the m7G score prediction model. Single-cell transcriptome sequencing (scRNA-seq) was used to assess the activation state of the m7G in the tumor microenvironment. Results: The m7RGs were highly expressed in tumors and most of the m7RGs are risk factors for prognosis. Moreover, the cellular pathway enrichment analysis suggested that m7G score was closely associated with invasion, cell cycle, DNA damage, and repair. In several cancers, m7G score was significantly negatively correlated with MSI and TMB and positively correlated with TIDE, suggesting an ICB marker potential. XGBoost-based pathomics model accurately predicts m7G scores with an area under the ROC curve (AUC) of 0.97. Analysis of scRNA-seq suggests that m7G differs significantly among cells of the tumor microenvironment. IHC confirmed high expression of EIF4E in breast cancer. The m7G prognostic model can accurately assess the prognosis of tumor patients with an AUC of 0.81, which was publicly hosted at https://pan-cancer-m7g.shinyapps.io/Panca-m7g/. Conclusion: The current study explored for the first time the m7G in pan-cancer and identified m7G as an innovative marker in predicting clinical outcomes and immunotherapeutic efficacy, with the potential for deeper integration with PPPM. Combining m7G within the framework of PPPM will provide a unique opportunity for clinical intelligence and new approaches. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00305-1.

Comprehensive pan-cancer analysis identifies cellular senescence as a new therapeutic target for cancer: multi-omics analysis and single-cell sequencing validation.

Although cellular senescence has long been recognized as an anti-tumor mechanism, mounting evidence suggests that in some circumstances, senescent cells promote tumor growth and malignancy spread. Therefore, research into the exact relationship between cellular senescence and tumor immunity is ongoing. We analyzed changes in the expression, copy number variation, single-nucleotide variation, methylation, and drug sensitivity of cellular senescence-related genes in 33 tumor types. The cellular senescence score was calculated using the single-sample gene-set enrichment analysis. The correlations between cellular senescence score and prognosis, tumor immune microenvironment (TIME), and expression of tumor immune-related genes were comprehensively analyzed. Single-cell transcriptome sequencing data were used to assess the activation state of cellular senescence in the tumor microenvironment (TME). The expression of cellular senescence-associated hub genes varied significantly across cancer types. In these genes, missense mutation was the major type of single nucleotide polymorphism, and heterozygous deletion and heterozygous amplification were the major types of copy number variation. Moreover, the cellular senescence pathway in tumors was sensitive to drugs such as XMD13-2, TPCA-1, methotrexate, and KIN001-102. Furthermore, the cellular senescence score was significantly higher in most cancer types, related to poor prognosis. The expression of immune checkpoint molecules such as NRP1, CD276, and CD44 was significantly correlated with the cellular senescence score. Monocyte cellular senescence was significantly higher in the TME of kidney renal clear cell carcinoma cells than in normal tissues. The findings of this study provide insights into the important role of cellular senescence in the TIME of human cancers and the effect of immunotherapy.

Prognostic and immunological role of SERPINH1 in pan-cancer.

Background: The SERPINH1 gene plays a vital part in tumorigenesis and development, whereas its potential as an immunotherapy target is still unknown. Hence, this research aimed to probe the roles of SERPINH1 in human tumors. Method: Using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) database, Oncomine, and SangerBox software, the pan-cancer expression of SERPINH1 and its correlation were systematically analyzed. SERPINH1 protein information was detected by the Human Protein Atlas (HPA) database and STRING database. The genomic alterations of SERPINH1 were studied using the c-BioPortal database. The influence of SERPINH1 on prognosis was analyzed using Kaplan-Meier plotter. The R package "clusterProfiler" was used for enrichment analysis to detect the role of SERPINH1. The TIMER2 database was used to further analyze the correlation between the immune cell infiltration score of TCGA samples and the expression of SERPINH1. Results: SERPINH1 overexpression was related to worse survival status in pan-cancer. In addition, high expression of SERPINH1 was positively associated with tumor stage and poor prognosis. Moreover, SERPINH1 played an important role in tumor microenvironment and immune regulation. Our study revealed that SERPINH1 expression has a strong correlation with immune cell filtration, immune regulation, chemokines, and immune checkpoints. Conclusion: Our research found that SERPINH1 was a risk factor and predictor of poor prognosis in various tumors. High expression of SERPINH1 may contribute to tumor immune-suppressive status. Also, SERPINH1 may become a potential immunotherapy target in pan-cancer.

An integrative analysis revealing POLD2 as a tumor suppressive immune protein and prognostic biomarker in pan-cancer.

Introduction: POLD2 is an indispensable subunit of DNA polymerase δ, which is responsible for the synthesis of the backward accompanying strand in eukaryotic organisms. Current studies have found an association between POLD2 and the development of a variety of cancers. However, its value in cancer immunotherapy has not been fully established. Methods: POLD2 expression was analyzed using RNA expression and clinical data from TCGA and GTEx databases. The prognostic impact of POLD2 on tumor patients was analyzed using clinical survival data from TCGA. Gene enrichment analysis was performed using the R package "cluster analyzer" to explore the role of POLD2. We used the TIMER2 database to analyze the relationship between immune cell infiltration and POLD2 expression in TCGA. We downloaded relevant data from TCGA and analyzed the relationship between POLD2 and immune checkpoints, immunosuppressive genes, immune activating genes, chemokines and chemokine receptors. Results: POLD2 was significantly overexpressed in most tumors compared to normal tissue. High POLD2 expression was significantly associated with advanced tumor stage, significantly shorter overall survival and progression-free survival. Also, we found that POLD2 expression correlated strongly with immunomodulatory genes, and significantly negatively with most immune checkpoints (PD-L1, CTLA4, TIM3, and CD28). Pathway enrichment analysis suggests that low expression of POLD2 promotes immune regulation-related pathways and high expression promotes metabolic and DNA repair-related pathways. Furthermore, tumor microenvironment analysis suggests that high POLD2 expression inhibits infiltration of CD8+ T cells and CD4+ memory T cells. Discussion: In conclusion, POLD2 may be a molecular biomarker for pan-cancer prognosis and immunotherapy. It may serve as a potential target for new insights in human tumor prognosis prediction and immunotherapy assessment.

Cross-sectional reference values of cerebral ventricle for Chinese neonates born at 25-41 weeks of gestation.

To establish the cross-sectional reference values of cerebral ventricular size for the Chinese newborns by the most correlated explanatory variables. The anterior horn width (AHW), thalamo-occipital distance (TOD), and ventricular index (VI) were collected prospectively from 1- to 7-day neonates without potential neurological problems. All neonates were delivered or treated at the Hunan Provincial Maternal and Child Health Care Hospital or Second Xiangya Hospital of Central South University between February and August 2021. The most correlated explanatory variables were identified with the max-min normalization and multiple regression. The reference values were then established based on the above variables. Additionally, intraclass correlation coefficients (ICC) were applied to evaluate the reliability of the overall data collection process. This prospective study consisted of 1848 neonates. The AHW was most highly correlated with GA; the TOD and VI were most strongly correlated with birth weight. All the foregoing correlations were positive ones. Heteroscedasticity and influential points existed in both TOD and VI. The ICCAHW was the largest to a specific rater or between raters, the ICCTOD the second largest, and the ICCVI the smallest. CONCLUSIONS: We recommend using the GA-based AHW reference values and birth weight-based TOD and VI ones. We also present a comparison of GA-based upper limits from all available reference intervals. Moreover, we determine that measurement errors are the primary cause of influential points and heteroscedasticity in TOD and VI studies and infer that the studies of TOD and VI are vulnerable to them. WHAT IS KNOWN: • Reference values of infantile cerebral ventricles are vital in diagnosing and treating cerebral ventricular dilatation. • Precursors established gestational age-based reference values subjectively. WHAT IS NEW: • We set cross-sectional reference values based on the most correlated variables for Chinese neonates and compared all available gestational age-based upper limits. • Influential points and heteroscedasticity mainly caused by measurement errors are common in TOD and VI studies.