The cell death-related genes machine learning model for precise therapy and clinical drug selection in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the prevailing subtype of hepatocellular malignancy. While previous investigations have evidenced a robust link with programmed cell death (PCD) and tumorigenesis, a comprehensive inquiry targeting the relationship between multiple PCDs and HCC remains scant. Our aim was to develop a predictive model for different PCD patterns in order to investigate their impact on survival rates, prognosis and drug response rates in HCC patients. We performed functional annotation and pathway analysis on identified PCD-related genes (PCDRGs) using multiple bioinformatics tools. The prognostic value of these PCDRGs was verified through a dataset obtained from GEO. Consensus clustering analysis was utilized to elucidate the correlation between diverse PCD clusters and pertinent clinical characteristics. To comprehensively uncover the distinct PCD regulatory patterns, our analysis integrated gene expression profiling, immune cell infiltration and enrichment analysis. To predict survival differences in HCC patients, we established a PCD model. To enhance the clinical applicability for the model, we developed a highly accurate nomogram. To address the treatment of HCC, we identified several promising chemotherapeutic agents and novel targeted drugs. These drugs may be effective in treating HCC and could improve patient outcomes. To develop a cell death feature for HCC patients, we conducted an analysis of 12 different PCD mechanisms using eligible data obtained from public databases. Through this analysis, we were able to identify 1254 PCDRGs likely to contribute to cell death on HCC. Further analysis of 1254 PCDRGs identified 37 genes with prognostic value in HCC patients. These genes were then categorized into two PCD clusters A and B. The categorization was based on the expression patterns of the genes in the different clusters. Patients in PCD cluster B had better survival probabilities. This suggests that PCD mechanisms, as represented by the genes in cluster B, may have a protective effect against HCC progression. Furthermore, the expression of PCDRGs was significantly higher in PCD cluster A, indicating that this cluster may be more closely associated with PCD mechanisms. Furthermore, our observations indicate that patients exhibiting elevated tumour mutation burden (TMB) are at an augmented risk of mortality, in comparison to those displaying low TMB and low-risk statuses, who are more likely to experience prolonged survival. In addition, we have investigated the potential distinctions in the susceptibility of diverse risk cohorts towards emerging targeted therapies, designed for the treatment of HCC. Moreover, our investigation has shown that AZD2014, SB505124, LJI308 and OSI-207 show a greater efficacy in patients in the low-risk category. Conversely, for the high-risk group patients, PD173074, ZM447439 and CZC24832 exhibit a stronger response. Our findings suggest that the identification of risk groups and personalized treatment selection could lead to better clinical outcomes for patients with HCC. Furthermore, significant heterogeneity in clinical response to ICI therapy was observed among HCC patients with varying PCD expression patterns. This novel discovery underscores the prospective usefulness of these expression patterns as prognostic indicators for HCC patients and may aid in tailoring targeted treatment for those of distinct risk strata. Our investigation introduces a novel prognostic model for HCC that integrates diverse PCD expression patterns. This innovative model provides a novel approach for forecasting prognosis and assessing drug sensitivity in HCC patients, driving a more personalized and efficacious treatment paradigm, elevating clinical outcomes. Nonetheless, additional research endeavours are required to confirm the model's precision and assess its potential to inform clinical decision-making for HCC patients.

Peroxisome proliferator-activated receptors signature reveal the head and neck squamous cell carcinoma energy metabolism phenotype and clinical outcome.

BACKGROUND: Peroxisome proliferator activating receptors (PPARs) are important regulators of nuclear hormone receptor function, and they play a key role in biological processes such as lipid metabolism, inflammation and cell proliferation. However, their role in head and neck squamous cell carcinoma (HNSC) is unclear. METHODS: We used multiple datasets, including TCGA-HNSC, GSE41613, GSE139324, PRJEB23709 and IMVigor, to perform a comprehensive analysis of PPAR-related genes in HNSC. Single-cell sequencing data were preprocessed using Seurat packets, and intercellular communication was analyzed using CellChat packets. Functional enrichment analysis of PPAR-related genes was performed using ClusterProfile and GSEA. Prognostic models were constructed using LASSO and Cox regression models, and immunohistochemical analyses were performed using human protein mapping (The Human Protein Atlas). RESULTS: Our single-cell RNA sequencing analysis revealed distinct cell populations in HNSC, with T cells having the most significant transcriptome differences between tumors and normal tissues. The PPAR features were higher in most cell types in tumor tissues compared with normal tissues. We identified 17 PPAR-associated differentially expressed genes between tumors and normal tissues. A prognostic model based on seven PPAR-associated genes was constructed with high accuracy in predicting 1, 2 and 3 year survival in patients with HNSC. In addition, patients with a low risk score had a higher immune score and a higher proportion of T cells, CD8+ T cells and cytotoxic lymphocytes. They also showed higher immune checkpoint gene expression, suggesting that they might benefit from immunotherapy. PPAR-related genes were found to be closely related to energy metabolism. CONCLUSIONS: Our study provides a comprehensive understanding of the role of PPAR related genes in HNSC. The identified PPAR features and constructed prognostic models may serve as potential biomarkers for HNSC prognosis and treatment response. In addition, our study found that PPAR-related genes can differentiate energy metabolism and distinguish energy metabolic heterogeneity in HNSC, providing new insights into the molecular mechanisms of HNSC progression and therapeutic response.

Leveraging diverse cell-death patterns to predict the clinical outcome of immune checkpoint therapy in lung adenocarcinoma: Based on muti-omics analysis and vitro assay.

Advanced LUAD shows limited response to treatment including immune therapy. With the development of sequencing omics, it is urgent to combine high-throughput multi-omics data to identify new immune checkpoint therapeutic response markers. Using GSE72094 (n = 386) and GSE31210 (n = 226) gene expression profile data in the GEO database, we identified genes associated with lung adenocarcinoma (LUAD) death using tools such as "edgeR" and "maftools" and visualized the characteristics of these genes using the "circlize" R package. We constructed a prognostic model based on death-related genes and optimized the model using LASSO-Cox regression methods. By calculating the cell death index (CDI) of each individual, we divided LUAD patients into high and low CDI groups and examined the relationship between CDI and overall survival time by principal component analysis (PCA) and Kaplan-Meier analysis. We also used the "ConsensusClusterPlus" tool for unsupervised clustering of LUAD subtypes based on model genes. In addition, we collected data on the expression of immunomodulatory genes and model genes for each cohort and performed tumor microenvironment analyses. We also used the TIDE algorithm to predict immunotherapy responses in the CDI cohort. Finally, we studied the effect of PRKCD on the proliferation and migration of LUAD cells through cell culture experiments. The study utilized the TCGA-LUAD cohort (n = 493) and identified 2,901 genes that are differentially expressed in patients with LUAD. Through KEGG and GO enrichment analysis, these genes were found to be involved in a wide range of biological pathways. The study also used univariate Cox regression models and LASSO regression analyses to identify 17 candidate genes that were best associated with mortality prognostic risk scores. By comparing the overall survival (OS) outcomes of patients with different CDI values, it was found that increased CDI levels were significantly associated with lower OS rates. In addition, the study used unsupervised cluster analysis to divide 115 LUAD patients into two distinct clusters with significant differences in OS timing. Finally, a prognostic indicator called CDI was established and its feasibility as an independent prognostic indicator was evaluated by Cox proportional risk regression analysis. The immunotherapy efficacy was more sensitive in the group with high expression of programmed cell death models. Relationship between programmed cell death (PCD) signature models and drug reactivity. After evaluating the median inhibitory concentration (IC50) of various drugs in LUAD samples, statistically significant differences in IC50 values were found in cohorts with high and low CDI status. Specifically, Gefitinib and Lapatinib had higher IC50 values in the high-CDI cohort, while Olaparib, Oxaliplatin, SB216763, and Axitinib had lower values. These results suggest that individuals with high CDI levels are sensitive to tyrosine kinase inhibitors and may be resistant to conventional chemotherapy. Therefore, this study constructed a gene model that can evaluate patient immunotherapy by using programmed cell death-related genes based on muti-omics. The CDI index composed of these programmed cell death-related genes reveals the heterogeneity of lung adenocarcinoma tumors and serves as a prognostic indicator for patients.

Comprehensive Evaluation of RNA and DNA Viromic Methods Based on Species Richness and Abundance Analyses Using Marmot Rectal Samples.

Viral metagenomics is the most powerful tool to profile viromic composition for a given sample. Different viromic methods, including amplification-free ones, have been developed, but choosing them for different purposes requires comprehensive benchmarks. Here, we assessed the performance of four routinely used methods, i.e., multiple displacement amplification (MDA), direct metagenomic sequencing (MTG), sequence-independent single-primer amplification (SIA), and metatranscriptomic sequencing (MTT), using marmot rectal samples as the templates spiked with five known viruses of different genome types. The obtained clean data were differently contaminated by host and bacterial genomes, resulting in MDA having the most, with ~72.1%, but MTT had only ~7.5% data, useful for follow-up viromic analysis. MDA showed a broader spectrum with higher efficiency to profile the DNA virome, and MTT captured almost all RNA viruses with extraordinary sensitivity; hence, they are advisable in richness-based viromic studies. MTG was weak in capturing single-stranded DNA viruses, and SIA could detect both RNA and DNA viruses but with high randomness. Due to biases to certain types of viruses, the four methods caused different alterations to species abundance compared to the initial virus composition. SIA and MDA introduced greater stochastic errors to relative abundances of species, genus, and family taxa, whereas the two amplification-free methods were more tolerant toward such errors and thus are recommendable in abundance-based analyses. In addition, genus taxon is a compromising analytic level that ensures technically supported and biologically and/or ecologically meaningful viromic conclusions. IMPORTANCE Viral metagenomics can be roughly divided into species richness-based studies and species abundance-based analyses. Viromic methods with different principles have been developed, but rational selection of these techniques according to different purposes requires comprehensive understanding of their properties. By assessing the four most widely used methods using template samples, we found that multiple displacement amplification (MDA) and metatranscriptomic sequencing (MTT) are advisable for species richness-based viromic studies, as they show excellent efficiency to detect DNA and RNA viruses. Meanwhile, metagenomic sequencing (MTG) and MTT are more compatible with stochastic errors of methods introduced into relative abundance of viromic taxa and hence are rational choices in species abundance-based analyses. This study also highlights that MTG needs to tackle host genome contamination and ameliorate the capacity to detect single-stranded DNA viruses in the future, and the MTT method requires an improvement in bacterial rRNA depletion prior to library preparation.

Extensive Genetic Diversity of Polyomaviruses in Sympatric Bat Communities: Host Switching versus Coevolution.

Polyomaviruses (PyVs) are small DNA viruses carried by diverse vertebrates. The evolutionary relationships of viruses and hosts remain largely unclear due to very limited surveillance in sympatric communities. In order to investigate whether PyVs can transmit among different mammalian species and to identify host-switching events in the field, we conducted a systematic study of a large collection of bats (n = 1,083) from 29 sympatric communities across China which contained multiple species with frequent contact. PyVs were detected in 21 bat communities, with 192 PyVs identified in 186 bats from 15 species within 6 families representing at least 28 newly described PyVs. Surveillance results and phylogenetic analyses surprisingly revealed three interfamily PyV host-switching events in these sympatric bat communities: two distinct PyVs were identified in two bat species in restricted geographical locations, while another PyV clustered phylogenetically with PyVs carried by bats from a different host family. Virus-host relationships of all discovered PyVs were also evaluated, and no additional host-switching events were found. PyVs were identified in different horseshoe bat species in sympatric communities without observation of host-switching events, showed high genomic identities, and clustered with each other. This suggested that even for PyVs with high genomic identities in closely related host species, the potential for host switching is low. In summary, our findings revealed that PyV host switching in sympatric bat communities can occur but is limited and that host switching of bat-borne PyVs is relatively rare on the predominantly evolutionary background of codivergence with their hosts.IMPORTANCE Since the discovery of murine polyomavirus in the 1950s, polyomaviruses (PyVs) have been considered highly host restricted in mammals. Sympatric bat communities commonly contain several different bat species in an ecological niche facilitating viral transmission, and they therefore represent a model to identify host-switching events of PyVs. In this study, we screened PyVs in a large number of bats in sympatric communities from diverse habitats across China. We provide evidence that cross-species bat-borne PyV transmission exists, though is limited, and that host-switching events appear relatively rare during the evolutionary history of these viruses. PyVs with close genomic identities were also identified in different bat species without host-switching events. Based on these findings, we propose an evolutionary scheme for bat-borne PyVs in which limited host-switching events occur on the background of codivergence and lineage duplication, generating the viral genetic diversity in bats.

Virome profiling of rodents in Xinjiang Uygur Autonomous Region, China: Isolation and characterization of a new strain of Wenzhou virus.

Rodents, as the most diverse and widest distributed mammals, are a natural reservoir of many zoonotic viruses. However, little is known about the viral diversity harbored by rodents in China. Here we performed viral metagenomic analyses of 314 wild rodents covering 7 species, sampled in North-western China. We also conducted a systematic virological characterization of a new Wenzhou virus (WENV) isolate, QARn1, from a brown rat (Rattus norvegicus). Full genomic and phylogenetic analyses showed that QARn1 is a previously unidentified strain of Wenzhou mammarenavirus and forms a new branch within the Asian clade. Experimental infection of Sprague-Dawley rats with QARn1 did not present overt pathology, but specific humoral immune responses developed and mild hemorrhage and immunocyte infiltration of the lungs and thymus were observed. These observations have expanded the geographic distribution of WENV to Central Asia, and further confirm that brown rats are natural hosts of Wenzhou virus.

Characterization and complete genome sequence analysis of a novel virulent Siphoviridae phage against Staphylococcus aureus isolated from bovine mastitis in Xinjiang, China.

Bovine mastitis is one of the most costly diseases in dairy cows worldwide. It can be caused by over 150 different microorganisms, where Staphylococcus aureus is the most frequently isolated and a major pathogen responsible for heavy economic losses in dairy industry. Although antibiotic therapy is most widely used, alternative treatments are necessary due to the increasing antibiotic resistance. Using phage for pathogen control is a promising tool in the fight against antibiotic resistance. Mainly using high-throughput sequencing, bioinformatics and our proposed phage termini identification method, we have isolated and characterized a novel virulent phage, designated as vB_SauS_IMEP5, from manure collected from dairy farms in Shihezi, Xinjiang, China, for use as a biocontrol agent against Staphylococcus aureus infections. Its latent period was about 30 min and its burst size was approximately 272PFU/cell. Phage vB_SauS_IMEP5 survives in a wide pH range between 3 and 12. A treatment at 70 °C for 20 min can inactive the phage. Morphological analysis of vB_SauS_IMEP5 revealed that phage vB_SauS_IMEP5 morphologically resembles phages in the family Siphoviridae. Among our tested multiplicity of infections (MOIs), the optimal multiplicity of infection (MOI) of this phage was determined to be 0.001, suggesting that phage vB_SauS_IMEP5 has high bacteriolytic potential and good efficiency for reducing bacterial growth. The complete genome of IME-P5 is a 44,677-bp, linear, double-stranded DNA, with a G+C content of 34.26%, containing 69 putative ORFs. The termini of genome were determined with next-generation sequencing data using our previously proposed termini identification method, which suggests that this phage has non-redundant termini with 9nt 3' protruding cohesive ends. The genomic and proteomic characteristics of IMEP5 demonstrate that this phage does not belong to any of the previously recognized Siphoviridae Staphylococcus phage groups, suggesting the creation of a new lineage, thus adding to the knowledge on the diversity of Staphylococcus phages. An N-acetylmuramoyl-L-alanine amidase gene and several conserved genes were predicted, while no virulence or antibiotic resistance genes were identified. This study isolated and characterized a novel S. aureus phage vB_SauS_IMEP5, and our findings suggest that this phage may be potentially utilized as a therapeutic or prophylactic candidate against S.aureus infections.

Host IQGAP1 and Ebola virus VP40 interactions facilitate virus-like particle egress.

We have identified host IQGAP1 as an interacting partner for Ebola virus (EBOV) VP40, and its expression is required for EBOV VP40 virus-like particle (VLP) budding. IQGAP1 is involved in actin cytoskeletal remodeling during cell migration and formation of filopodia. The physical interaction and the functional requirement for IQGAP1 in EBOV VP40 VLP egress link virus budding to the cytoskeletal remodeling machinery. Consequently, this interaction represents a novel target for development of therapeutics to block budding and transmission of filoviruses.

Migration of Norway rats resulted in the worldwide distribution of Seoul hantavirus today.

Despite the worldwide distribution, most of the known Seoul viruses (SEOV) are closely related to each other. In this study, the M and the S segment sequences of SEOV were recovered from 130 lung tissue samples (mostly of Norway rats) and from six patient serum samples by reverse transcription-PCR. Genetic analysis revealed that all sequences belong to SEOV and represent 136 novel strains. Phylogenetic analysis of all available M and S segment sequences of SEOV, including 136 novel Chinese strains, revealed four distinct groups. All non-Chinese SEOV strains and most of the Chinese variants fell into the phylogroup A, while the Chinese strains originating from mountainous areas clustered into three other distinct groups (B, C, and D). We estimated that phylogroup A viruses may have arisen only within the last several centuries. All non-Chinese variants appeared to be directly originated from China. Thus, phylogroup A viruses distributed worldwide may share a recent ancestor, whereas SEOV seems to be as diversified genetically as other hantaviruses. In addition, all available mitochondrial DNA (mtDNA) sequences of Norway rats, including our 44 newly recovered mtDNA sequences, were divided into two phylogenetic groups. The first group, which is associated with the group A SEOV variants, included most of rats from China and also all non-Chinese rats, while the second group consisted of a few rats originating only from mountain areas in China. We hypothesize that an ancestor of phylogroup A SEOV variants was first exported from China to Europe and then spread through the New World following the migration of Norway rats.

[Isolation and characterization of Hantavirus carried by rodents in Huludao, Liaoning province].

OBJECTIVE: To investigate the Hantavirus infection and their genotype in rodents in Huludao. METHODS: Rodents were collected from the main epidemic areas to detect antigen of Hantavirus in rat lungs by indirect immunofluorescence assay. Antigen-positive samples were inoculated onto cultures of confluent Vero E6 cells for the isolation of virus. The genotypes of viruses in all antigen-positive samples were identified by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: 200 rats were collected in the main epidemic areas, and 11 Hantavirus-positive samples were tested. The positive rate of Hantavirus in rats was 5.5%. Three strains of Hantavirus were isolated in Vero E6 cell culture. Data from the phylogenetic trees constructed by partial S segment (620-999 nt) or partial G1 segment (180-580 nt) showed that the three isolates carried by rats from Huludao were all genetic subtype SEOV 3. Furthermore, the phylogenetic tree constructed by partial G2 segment (2003-2302 nt) divided SEOV strains into 7 genetic subtypes, and the three isolates were having a closer evolutionary relationship with isolates CP211, ch302 and dc501 from Beijing, and the isolates SD10 and SD227 form Shandong. CONCLUSION: Data indicated that the rate of carrying virus was high and the main genetic subtype of Hantavirus was S3 of Seoul virus in Huludao area.

[The epidemic characteristics and preventive measures of hemorrhagic fever with syndromes in China].

OBJECTIVE: To summarize and analyze the epidemic situation of hantaviruses including geographic distribution, types and prevalent intensity of epidemic areas of hantavirus for the last 30 years in China, and to discuss relative preventive measures. METHODS: Collecting and analyzing the data of hantaviruses epidemics in China. RESULTS: The annual number of cases of hantavirus disease rapidly increased from 3295 in 1970 to 115,804 in 1986 then sustained between 40,000 and 60,000 cases annually in the 1990's, and then decreased thereafter. The epidemic areas existed in all provinces except Qinhai and Xinjiang and there were the hospitalized cases of hantavirus disease reported in other provinces. In recent years, the prevalence of hantavirus infection had increased in some cities, and the seasonal distribution of the cases changed as well. CONCLUSION: Data suggested that the new epidemic characteristics of hantaviruses had emerged in China suggesting that it was necessary to strengthen surveillance programs and to take comprehensive preventive measures for the control and prevention of hantaviruses in China.