Pan-cancer Comprehensive Analysis Identified EGFR as a Potential Biomarker for Multiple Tumor Types.

The epidermal growth factor receptor (EGFR) has been extensively studied for its critical role in the development and progression of various malignancies. In this comprehensive pan-cancer analysis, we investigated the potential of EGFR as a biomarker across multiple tumor types; a comprehensive analysis of EGFR gene mutation and copy number variation was conducted using cBioPortal and other tools. Utilizing multi-omics datasets from The Cancer Genome Atlas (TCGA), we analyzed EGFR's expression patterns, prognostic implications, genetic mutations, and molecular interactions in different cancers. Our findings revealed frequent dysregulation of EGFR in several tumor types, including lung cancers and glioblastoma multiforme. High EGFR expression was consistently associated with poor clinical outcomes, such as reduced overall survival, disease-free survival, and progression-free survival. Genetic alteration analysis indicated a high frequency of EGFR mutations and copy number variations, particularly in glioblastoma multiforme. Additionally, our study suggests a complex relationship between EGFR expression and cancer-associated fibroblast infiltration, which may contribute to an immunosuppressive tumor microenvironment. These findings underscore the clinical relevance of EGFR as a prognostic biomarker and therapeutic target, emphasizing the need for further research and the development of targeted therapies to enhance patient outcomes in cancers with EGFR alterations. The co-expression network of EGFR with genes and proteins involved in cell cycle regulation and mitotic control provided insights into the molecular mechanisms of oncogenesis.

Pan-immune-inflammation value as a prognostic biomarker for colon cancer and its variation by primary tumor location.

BACKGROUND: A growing body of research indicates significant differences between left-sided colon cancers (LCC) and right-sided colon cancers (RCC). Pan-immune-inflammation value (PIV) is a systemic immune response marker that can predict the prognosis of patients with colon cancer. However, the specific distinction between PIV of LCC and RCC remains unclear. AIM: To investigate the prognostic and clinical significance of PIV in LCC and RCC patients. METHODS: This multicenter retrospective cohort study included 1510 patients with colon cancer, comprising 801 with LCC and 709 with RCC. We used generalized lifting regression analysis to evaluate the relative impact of PIV on disease-free survival (DFS) in these patients. Kaplan-Meier analysis, as well as univariate and multivariate analyses, were used to examine the risk factors for DFS. The correlation between PIV and the clinical characteristics was statistically analyzed in these patients. RESULTS: A total of 1510 patients {872 female patients (58%); median age 63 years [interquartile ranges (IQR): 54-71]; patients with LCC 801 (53%); median follow-up 44.17 months (IQR 29.67-62.32)} were identified. PIV was significantly higher in patients with RCC [median (IQR): 214.34 (121.78-386.72) vs 175.87 (111.92-286.84), P < 0.001]. After propensity score matching, no difference in PIV was observed between patients with LCC and RCC [median (IQR): 182.42 (111.88-297.65) vs 189.45 (109.44-316.02); P = 0.987]. PIV thresholds for DFS were 227.84 in LCC and 145.99 in RCC. High PIV (> 227.84) was associated with worse DFS in LCC [PIV-high: Adjusted hazard ratio (aHR) = 2.39; 95% confidence interval: 1.70-3.38; P < 0.001] but not in RCC (PIV-high: aHR = 0.72; 95% confidence interval: 0.48-1.08; P = 0.114). CONCLUSION: These findings suggest that PIV may predict recurrence in patients with LCC but not RCC, underscoring the importance of tumor location when using PIV as a colon cancer biomarker.

Retrospect and prospect of Nicotiana tabacum genome sequencing.

Investigating plant genomes offers crucial foundational resources for exploring various aspects of plant biology and applications, such as functional genomics and breeding practices. With the development in sequencing and assembly technology, several Nicotiana tabacum genomes have been published. In this paper, we reviewed the progress on N. tabacum genome assembly and quality, from the initial draft genomes to the recent high-quality chromosome-level assemblies. The application of long-read sequencing, optical mapping, and Hi-C technologies has significantly improved the contiguity and completeness of N. tabacum genome assemblies, with the latest assemblies having a contig N50 size over 50 Mb. Despite these advancements, further improvements are still required and possible, particularly on the development of pan-genome and telomere-to-telomere (T2T) genomes. These new genomes will capture the genomic diversity and variations among different N. tabacum cultivars and species, and provide a comprehensive view of the N. tabacum genome structure and gene content, so to deepen our understanding of the N. tabacum genome and facilitate precise breeding and functional genomics.

Identification of nitrile-containing isoquinoline-related natural product derivatives as coronavirus entry inhibitors in silico and in vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections and deaths worldwide since its emergence in Wuhan, China, in late 2019. Natural product inhibitors targeting the interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2 (ACE2), crucial for viral attachment and cellular entry, are of significant interest as potential antiviral agents. In this study a library of nitrile- and sulfur-containing natural product derived compounds were used for virtual drug screening against the RBD of the SARS-CoV-2 spike protein. The top 18 compounds from docking were tested for their efficacy to inhibit virus entry. In vitro experiments revealed that compounds 9, 14, and 15 inhibited SARS-CoV-2 pseudovirus and live virus entry in HEK-ACE2 and Vero E6 host cells at low micromolar IC50 values. Cell viability assays showed these compounds exerted low cytotoxicity towards MRC5, Vero E6, and HEK-ACE2 cell lines. Microscale thermophoresis revealed all three compounds strongly bound to the RBDs of SARS-CoV-2, SARS-CoV-2 XBB, SARS-CoV-1, MERS-CoV, and HCoV-HKU1, with their Kd values increasing as RBD sequence similarity decreased. Molecular docking studies indicated compounds 9, 14, and 15 bound to the SARS-CoV-2 spike protein RBD and interacted with hotspot amino acid residues required for the RBD-ACE2 interaction and cellular infection. These three nitrile-containing candidates, particularly compound 15, should be considered for further development as potential pan-coronavirus entry inhibitors.

Prevalence of Drug Resistance Associated Substitutions in Persons With Chronic Hepatitis C Infection and Virological Failure Following Initial or Re-treatment With Pan-genotypic Direct-Acting Antivirals: A Systematic Review and Meta-analysis.

BACKGROUND: The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%-12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy. METHODS: We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis. RESULTS: The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0-92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0-93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0-87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0-99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0-100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors. DISCUSSION: At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment.

Pan-cancer characterization of cellular senescence reveals its inter-tumor heterogeneity associated with the tumor microenvironment and prognosis.

Cellular senescence (CS) is characterized by the irreversible cell cycle arrest and plays a key role in aging and diseases, such as cancer. Recent years have witnessed the burgeoning exploration of the intricate relationship between CS and cancer, with CS recognized as either a suppressing or promoting factor and officially acknowledged as one of the 14 cancer hallmarks. However, a comprehensive characterization remains absent from elucidating the divergences of this relationship across different cancer types and its involvement in the multi-facets of tumor development. Here we systematically assessed the cellular senescence of over 10,000 tumor samples from 33 cancer types, starting by defining a set of cancer-associated CS signatures and deriving a quantitative metric representing the CS status, called CS score. We then investigated the CS heterogeneity and its intricate relationship with the prognosis, immune infiltration, and therapeutic responses across different cancers. As a result, cellular senescence demonstrated two distinct prognostic groups: the protective group with eleven cancers, such as LIHC, and the risky group with four cancers, including STAD. Subsequent in-depth investigations between these two groups unveiled the potential molecular and cellular mechanisms underlying the distinct effects of cellular senescence, involving the divergent activation of specific pathways and variances in immune cell infiltrations. These results were further supported by the disparate associations of CS status with the responses to immuno- and chemo-therapies observed between the two groups. Overall, our study offers a deeper understanding of inter-tumor heterogeneity of cellular senescence associated with the tumor microenvironment and cancer prognosis.

Pan-genome-scale metabolic modeling of Bacillus subtilis reveals functionally distinct groups.

Bacillus subtilis is an important industrial and environmental microorganism known to occupy many niches and produce many compounds of interest. Although it is one of the best-studied organisms, much of this focus including the reconstruction of genome-scale metabolic models has been placed on a few key laboratory strains. Here, we substantially expand these prior models to pan-genome-scale, representing 481 genomes of B. subtilis with 2,315 orthologous gene clusters, 1,874 metabolites, and 2,239 reactions. Furthermore, we incorporate data from carbon utilization experiments for eight strains to refine and validate its metabolic predictions. This comprehensive pan-genome model enables the assessment of strain-to-strain differences related to nutrient utilization, fermentation outputs, robustness, and other metabolic aspects. Using the model and phenotypic predictions, we divide B. subtilis strains into five groups with distinct patterns of behavior that correlate across these features. The pan-genome model offers deep insights into B. subtilis' metabolism as it varies across environments and provides an understanding as to how different strains have adapted to dynamic habitats. IMPORTANCE: As the volume of genomic data and computational power have increased, so has the number of genome-scale metabolic models. These models encapsulate the totality of metabolic functions for a given organism. Bacillus subtilis strain 168 is one of the first bacteria for which a metabolic network was reconstructed. Since then, several updated reconstructions have been generated for this model microorganism. Here, we expand the metabolic model for a single strain into a pan-genome-scale model, which consists of individual models for 481 B. subtilis strains. By evaluating differences between these strains, we identified five distinct groups of strains, allowing for the rapid classification of any particular strain. Furthermore, this classification into five groups aids the rapid identification of suitable strains for any application.

Comparative efficacy of THR-ß agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis.

AIMS: To compare the efficacy of thyroid hormone receptor beta (THR-ß) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. RESULTS: Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] -51.47; 95 % confidence interval [CI]: -68.25 to -34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD -47.08; 95 % CI: -58.83 to -35.34; SUCRA 75.5), GLP-1R agonists (MD -37.36; 95 % CI: -69.52 to -5.21; SUCRA 52.3) and THR-ß agonists (MD -33.20; 95 % CI: -43.90 to -22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD -9.65; 95 % CI: -19.28 to -0.01; SUCRA 82.2) vs. placebo, followed by THR-ß agonists (MD -5.79; 95 % CI: -9.50 to -2.09; SUCRA 58.2), and GLP-1RAs (MD -5.58; 95 % CI: -15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-ß agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-ß agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-ß agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. CONCLUSION: These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

The relationship between early-onset preeclampsia and the prognostic nutritional index and inflammatory markers.

BACKGROUND: Preeclampsia is still a disease whose cause and treatment have not been fully characterised. Early-onset preeclampsia occurs before the 34th week of pregnancy, and late-onset preeclampsia occurs at 34 weeks or older. In our study, we investigated whether the prognostic nutritional index (PNI) and pan immune inflammation value (PIV), which are used in the prognosis and prediction of diseases in new studies in the literature, are useful for predicting early-onset preeclampsia. METHODS: The first group consisted of healthy pregnant women who had a single foetus without any additional disease between 24 and 34 gestational weeks, and the second group consisted of pregnant women who were diagnosed with early-onset preeclampsia and did not have any additional disease or foetal anomalies during the same gestational week. Neutrophil, lymphocyte, monocyte, thrombocyte, ALB, pan immune inflammation value (PIV) and prognostic nutritional index (PNI) scores were recorded. RESULTS: In our case control study, 70 patients with early-onset preeclampsia and 140 pregnant women composed the normotensive (control) group. There was a significant difference between the groups according to PIV (p = 0.04). The prognostic nutritional index (PNI) was significantly lower in the early-onset preeclampsia group than in the normotensive group (p < 0,001). A PNI lower than 36, 30 could only predict early-onset preeclampsia with a low sensitivity of 31.1% and specificity of 45%; the area under the curve was 0,24 (95% confidence interval 0.18-0.31), p < 0,001. CONCLUSION: Patients with PNI scores lower than 36,30 may have early-onset preeclampsia.

Preeclampsia, often referred to as pregnancy poisoning, is a condition that is life-threatening to the mother and baby. It typically develops after the 20th week of pregnancy and is characterised by high blood pressure and deterioration in blood values. Preeclampsia comes in two forms: early and late. The early form occurs before the 34th week and tends to be more severe than the late form, causing narrowing of the vessels supplying the baby, decreased blood flow, and delayed foetal development. The late form commonly appears after the 34th week and is usually milder. Since the early form carries a higher risk and often requires premature delivery of the foetus or termination of the pregnancy, studies are being conducted on its prevention and treatment. This study aimed to investigate the differences in blood parameters between patients with early-onset preeclampsia and pregnant women with normal blood pressure and to assess for differences between both groups.

CISD3 is a prognostic biomarker and therapeutic target in pan-cancer.

Recent studies indicate that CISD3 is crucial in mitochondrial function and tumorigenesis. Using various databases, we systematically analyzed its expression, prognostic value, and immune activity. Our findings show CISD3 is mainly expressed in tumor cells across cancers, with higher mRNA but lower protein levels, degraded post-translationally via the lysosomal pathway. In certain cancers, CISD3 expression is positively correlated with tumor-infiltrating immune cells. Prognostic analysis suggests dual roles as both protective and risk factors, notably an independent prognostic predictor in renal cell carcinoma (RCC). CISD3 copy number variations are linked to homologous recombination defects and tumor-specific neoantigens, negatively correlated with methylation levels. Pathway analysis reveals CISD3 involvement in oncogenic processes, such as proliferation inhibition and epithelial-mesenchymal transition. Protein interactions underline its role in mitochondrial metabolism and redox balance. Experiments confirm low CISD3 expression in cancers, with overexpression reducing proliferation, migration, invasion, and tumor growth in mice. Mechanistic studies indicate CISD3 overexpression disrupts mitochondrial function, increases ROS levels, decreases GSH/GSSG ratios and mitochondrial membrane potential, inhibiting antioxidant activity and promoting cell damage and ferroptosis, thus impeding cancer progression. This study highlights CISD3's potential as a prognostic biomarker and therapeutic target.

The Evolution of Extreme Genetic Variability in a Parasite-Resistance Complex.

Genomic regions that play a role in parasite defense are often found to be highly variable, with the MHC serving as an iconic example. Single nucleotide polymorphisms may represent only a small portion of this variability, with Indel polymorphisms and copy number variation further contributing. In extreme cases, haplotypes may no longer be recognized as orthologous. Understanding the evolution of such highly divergent regions is challenging because the most extreme variation is not visible using reference-assisted genomic approaches. Here we analyze the case of the Pasteuria Resistance Complex (PRC) in the crustacean Daphnia magna, a defense complex in the host against the common and virulent bacterium Pasteuria ramosa. Two haplotypes of this region have been previously described, with parts of it being non-homologous, and the region has been shown to be under balancing selection. Using pan-genome analysis and tree reconciliation methods to explore the evolution of the PRC and its characteristics within and between species of Daphnia and other Cladoceran species, our analysis revealed a remarkable diversity in this region even among host species, with many non-homologous hyper-divergent-haplotypes. The PRC is characterized by extensive duplication and losses of Fucosyltransferase (FuT) and Galactosyltransferase (GalT) genes that are believed to play a role in parasite defense. The PRC region can be traced back to common ancestors over 250 million years. The unique combination of an ancient resistance complex and a dynamic, hyper-divergent genomic environment presents a fascinating opportunity to investigate the role of such regions in the evolution and long-term maintenance of resistance polymorphisms. Our findings offer valuable insights into the evolutionary forces shaping disease resistance and adaptation, not only in the genus Daphnia, but potentially across the entire Cladocera class.

SNRPB2 in the pan-cancer landscape: A bioinformatics exploration and validation in hepatocellular carcinoma.

Aberrant splicing is a significant contributor to gene expression abnormalities in cancer. SNRPB2, a component of U2 small nuclear ribonucleoprotein particles (snRNPs), contributes to the assembly of the spliceosome, the molecular machinery responsible for splicing. To date, few studies have investigated the role of SNRPB2 in tumorigenesis. We examined data sourced from various public databases, such as The Cancer Genome Atlas(TCGA), the Clinical Proteomic Tumor Analysis Consortium(CPTAC), and Gene Expression Omnibus(GEO). Our investigation included gene expression, genomic and epigenomic scrutiny, gene set enrichment assessment(GSEA), and immune cell infiltration evaluation. Furthermore, we performed empirical validation to ascertain the impact of SNRPB2 suppression on the proliferation and migration of liver cancer cells. Analysis of gene expression revealed widespread upregulation of SNRPB2 across a spectrum of cancer types, with heightened levels of SNRPB2 expression in numerous tumors linked to unfavorable prognosis. Genomic and epigenomic assessments revealed connections between SNRPB2 expression and variations in SNRPB2 copy number, DNA methylation patterns, and RNA modifications. Through gene set enrichment analysis, the involvement of SNRPB2 in vital biological processes and pathways related to cancer was identified. Furthermore, scrutiny of immune cell infiltration suggested a potential relationship between SNRPB2 and the tumor microenvironment, which was reinforced by multiple single-cell sequencing profiles. Subsequent experimental validation revealed that silencing SNRPB2 effectively impeded the proliferation and migration of liver cancer cells. Taken together, these findings underscore the prospective utility of SNRPB2 as a prognostic biomarker and a promising candidate for immunotherapy in cancer. It is necessary to engage in additional exploration into its underlying mechanisms and clinical treatment potential.

Decoding the Rarity: A Unique Case of Clear-Cell Variant of Oral Squamous Cell Carcinoma.

The clear-cell variant of oral squamous cell carcinoma is an extremely rare histological variant and an incompletely understood entity. Clear cell appearance in squamous cell carcinoma may be attributed to hydropic degeneration of neoplastic cells. We report a case of a 32-year-old male patient who presented with an ulceroproliferative growth in the left maxillary posterior region on the hard palate and gingiva, obliterating the buccal vestibule. Histopathologic examination revealed thick anastomosing strands of round to ovoid neoplastic cells with predominantly clear cytoplasm and marked cellular and nuclear pleomorphism infiltrating into the fibro-cellular connective tissue stroma. Special staining and immunohistochemistry (IHC) were performed to rule out the differentials of clear-cell variants of different sites such as salivary gland, odontogenic origin, and metastatic tumors. The clear cells were negative for periodic acid Schiff (PAS) and mucicarmine. The malignant clear cells showed positive reactions with IHC markers pan-cytokeratin and P63 and yielded negative results for S100 and CD10, confirming the diagnosis as a clear-cell variant of oral squamous cell carcinoma. We emphasize the importance of prompt and comprehensive diagnostic work-up to identify this rare, aggressive, and possibly fatal neoplasm.

Pan-cancer analysis of the prognostic and immunological roles of SHP-1/ptpn6.

SHP-1, a nonreceptor protein tyrosine phosphatase encoded by ptpn6, has been regarded as a regulatory protein of hematopoietic cell biology for years. However, there is now increasing evidence to support its role in tumors. Thus, the role of ptpn6 for prognosis and immune regulation across 33 tumors was investigated, aiming to explore its functional heterogeneity and clinical significance in pan-cancer. Differential expression of ptpn6 was found between cancer and adjacent normal tissues, and its expression was significantly correlated with the prognosis of tumor patients. In most cancers, ptpn6 expression was significantly associated with immune infiltration. This was further confirmed by ptpn6-related genes/proteins enrichment analysis. Additionally, genetic alterations in ptpn6 was observed in most cancers. As for epigenetic changes, it's phosphorylation levels significantly altered in 6 tumors, while methylation levels significantly altered in 12 tumors. Notably, the methylation levels of ptpn6 were significantly decreased in 11 tumors, accompanied by its increased expression in 8 of them, suggesting that the hypomethylation may be related to its increased expression. Our results show that ptpn6 plays a specific role in tumor immunity and exerts a pleiotropic effect in a variety of tumors. It can serve as a prognostic factor for some cancers. Especially in LGG, KIRC, UCS and TGCT, the increased expression of ptpn6 is associated with poor prognosis and high immune infiltration. This aids in understanding the role of ptpn6 in tumor biology, and can provide insight into presenting a potential biomarker for poor prognosis and immune infiltration in cancers.

Lymphocyte activation gene 3 served as a potential prognostic and immunological biomarker across various cancer types: a clinical and pan-cancer analysis.

Objectives: Lymphocyte activation gene 3 (LAG3), an inhibitory receptor in T-cell activation, is a negative prognostic factor. However, its impact on tumours has yet to be comprehensively elucidated on a pan-cancer scale. Thus, we aim to reveal its role at the pan-cancer level. Methods: We performed IHC staining on a retrospective cohort of 370 patients. Then we assessed the prognostic effect of LAG3 using Kaplan-Meier survival analysis and multivariate Cox regression analysis. In pan-cancer analysis, we constructed competing endogenous RNA and protein-protein interaction networks, conducted gene set enrichment analysis and identified correlations between LAG3 gene expression and various factors, including clinical characteristics, tumour purity, mutations, tumour immunity and drug sensitivity across 33 cancer types. Results: LAG3 was expressed higher in normal kidney tissues than in tumours. A high level of LAG3 gene expression was an independent prognostic factor for OS (HR = 6.60, 95% CI = 2.43-17.90, P < 0.001) and PFS (HR = 3.44, 95% CI = 1.68-7.10, P < 0.001). In pan-cancer analysis, LAG3 exhibited robust correlations with survival and tumour stages in various cancers. Moreover, LAG3 was strongly associated with immune-related genes, proteins and signalling pathways. LAG3 gene expression was positively associated with increased infiltration of activated immune cells and decreased infiltration of several resting cells. LAG3 gene expression was associated with tumour mutation burden and microsatellite instability in multiple cancers. Conclusion: High LAG3 gene expression was an independent risk factor in kidney neoplasms. It also functioned as a biomarker for prognosis, TIME and immunotherapy efficacy in the pan-cancer dimension.

Identification and Functional Annotation of Hypothetical Proteins of Pan-Drug-Resistant Providencia rettgeri Strain MRSN845308 Toward Designing Antimicrobial Drug Targets.

Providencia rettgeri has increasingly been responsible for several infections, including urinary tract, post-burn wounds, neonatal sepsis, and others. The emergence of drug-resistant isolates of P rettgeri, accompanied by intrinsic and acquired antibiotic resistance, has exacerbated the challenge of treating such infections, necessitating the development of novel therapeutics. Hypothetical proteins (HPs) form a major portion of cellular proteins and can be targeted by these novel therapeutics. In this study, 410 HPs from a pan-drug-resistant (PDR) P rettgeri strain (MRSN845308) were functionally annotated and characterized by physicochemical properties, localization, virulence, essentiality, druggability, and functionality. Among 410 HPs, the VirulentPred 2.0 tool and VICMpred combinedly predicted 33 HPs as virulent, whereas 48 HPs were highly interacting proteins based on the STRING v12 database. BlastKOALA and eggNOG-mapper v2.1.12 predicted 13 HPs involved in several metabolic pathways like Riboflavin metabolism and Lipopolysaccharide biosynthesis. Overall, 83 HPs were selected as primary drug targets; however, only 80 remained after nonhomology searching and essentiality analysis. In addition, all were detected as novel drug targets according to DrugBank 5.1.12. Considering the potential of membrane and extracellular proteins, 29 HPs (extracellular, outer, and inner membrane) were selected based on the combined prediction from PSORTb v3.0.3, CELLO v.2.5, BUSCA, SOSUIGramN, and PSLpred. According to the prevalence of those HPs in different strains of P rettgeri sequences in National Center for Biotechnology Information Identical Protein Groups (NCBI-IPG), 5 HPs were selected as final drug targets. In addition, 5 other HPs annotated as transporter proteins were also added to the list. As no crystal structures of our targets are present, 3-dimensional structures of selected HPs were predicted by the AlphaFold Server powered by AlphaFold 3. Our findings might facilitate a better understanding of the mechanism of virulence and pathogenesis, and up-to-date annotations can make uncharacterized HPs easy to identify as targets for novel therapeutics.

Deciphering EIF3D's Role in Immune Regulation and Malignant Progression: A Pan-Cancer Analysis with a Focus on Colon Adenocarcinoma.

Background: EIF3D, a key component of the eukaryotic translation initiation factor 3 (EIF3) complex, is critical in selectively translating mRNAs with atypical cap structures. Its relationship with colon adenocarcinoma (COAD) development and immune infiltration, however, remains under-explored. This study delves into EIF3D's role in COAD using bioinformatics and in vitro experimentation. Materials and Methods: We analyzed EIF3D expression levels utilizing TCGA, GTEx, CPTAC, and TISIDB databases. The TISCH database and ssGSEA method helped in assessing EIF3D's link with the tumor immune microenvironment. EIF3D expression in CRC cells was gauged via real-time PCR. Cell proliferation was assessed using CCK8 and colony formation assays, while migration capabilities were tested through Transwell assays. Flow cytometry facilitated cell cycle distribution and apoptosis analysis. ChIP-qPCR identified transcription factors regulating EIF3D, and bulk sequencing explored EIF3D's pathways in promoting COAD. Results: EIF3D upregulation is a common feature in various tumors, especially in COAD, correlating with poor prognosis in many cancer types. It showed significant associations with immune cell and cancer-associated fibroblast (CAF) infiltration across multiple tumors. Additionally, it is closely associated with molecular and immune subtypes of multiple tumors, including COAD. Single-cell analyses depicted EIF3D's distribution and proportion in CRC immune cells. In vitro findings indicated EIF3D knockdown curtailed proliferation and migration, inducing G0/G1 arrest in COAD cells. Moreover, bulk sequencing revealed EIF3D knockdown interferes with multiple cancer-related pathways, likely by curtailing cell cycle and DNA replication activities to regulate cell proliferation. Conclusion: EIF3D emerges as a potential prognostic biomarker for tumor progression and immune infiltration, particularly in COAD, potentially predicting immunotherapy efficacy. Additionally, EIF3D represents a multifaceted target implicated in COAD's malignant progression.

Comprehensive pan-cancer analysis and experiments revealed R3HDM1 as a novel predictive biomarker for prognosis and immune therapy response.

Background: R3HDM1, an RNA binding protein with one R3H domain, remains uncharacterized in terms of its association with tumor progression, malignant cell regulation, and the tumor immune microenvironment. This paper aims to fill this gap by analyzing the potential of R3HDM1 in diagnosis, prognosis, chemotherapy, and immune function across various cancers. Methods: Data was collected from the Firehost database (http://gdac.broadinstitute.org) to obtain the TCGA pan-cancer queue containing tumor and normal samples. Additional data on miRNA, TCPA, mutations, and clinical information were gathered from the UCSC Xena database (https://xenabrowser.net/datapages/). The mutation frequency and locus of R3HDM1 in the TCGA database were examined using the cBioPortal. External validation through GEO data was conducted to assess the differential expression of R3HDM1 in different cancers. Protein expression levels were evaluated using the Clinical Proteomics Tumor Analysis Alliance (CPTAC). The differential expression of R3HDM1 was verified in lung adenocarcinoma cell lines and normal lung glandular epithelial cells via RT-qPCR. Cell migration and proliferation experiments were conducted by knocking down the expression of R3HDM1 in two lung adenocarcinoma cell lines using small interfering RNA. The biological role of R3HDM1 in pan-cancer was explored using the GSEA method. Multiple immune infiltration algorithms from the TIMER2.0 database was employed to investigate the correlation between R3HDM1 expression and the tumor immune microenvironment. Validation of transcriptome immune infiltration was based on 140 single-cell datasets from the TISCH database. The study also characterized a pan-cancer survival profile and analyzed the differential expression of R3HDM1 in different molecular subtypes. The relationship between R3HDM1 and drug resistance was investigated using four chemotherapy data sources: CellMiner, GDSC, CTRP and PRISM. The impact of chemicals on the expression of R3HDM1 was explored through the CTD database. Result: The study revealed differential expression of R3HDM1 in various tumors, indicating its potential as an early diagnostic marker. Changes in somatic copy number (SCNA) and DNA methylation were identified as factors contributing to abnormal expression levels. Additionally, the study found that R3HDM1 expression is associated with clinical features, metabolic pathways, and important pathways related to metastasis and the immune system. High expression of R3HDM1 was linked to poor prognosis across different tumors and altered drug sensitivity. Furthermore, the expression of R3HDM1 showed significant correlations with immune modulatory molecules and biomarkers of lymphocyte subpopulation infiltration. Finally, the study highlighted four chemicals that could influence the expression of R3HDM1. Conclusion: Overall, this study proposes that R3HDM1 expression is a promising biomarker for predicting the prognosis of cancer, especially lung adenocarcinoma, and the efficacy of immunotherapy, demonstrating the rationale for further exploration in the development of anti-tumor therapies.

WGS Analysis of Staphylococcus warneri Outbreak in a Neonatal Intensive Care Unit.

Purpose: Staphylococcus warneri is an opportunistic pathogen responsible for hospital-acquired infections (HAIs). The aim of this study was to describe an outbreak caused by S. warneri infection in a neonatal intensive care unit (NICU) and provide investigation, prevention and control strategies for this outbreak. Methods: We conducted an epidemiological investigation of the NICU S. warneri outbreak, involving seven neonates, staff, and environmental screening, to identify the source of infection. WGS analyses were performed on S. warneri isolates, including species identification, core genome single-nucleotide polymorphism (cgSNP) analysis, pan-genome analysis, and genetic characterization assessment of the prevalence of specific antibiotic resistance and virulence genes. Results: Eight S. warneri strains were isolated from this outbreak, with seven from neonates and one from environment. Six clinical cases within three days in 2021 were linked to one strain isolated from environmental samples; isolates varied by 0-69 SNPs and were confirmed to be from an outbreak through WGS. Multiple infection prevention measures were implemented, including comprehensive environmental disinfection and stringent protocols, and all affected neonates were transferred to the isolation wards. Following these interventions, no further cases of S. warneri infections were observed. Furthermore, pan-genome analysis results suggested that in human S. warneri may exhibit host specificity. Conclusion: The investigation has revealed that the outbreak was linked to the milk preparation workbench by the WGS. It is recommended that there be a stronger focus on environmental disinfection management in order to raise awareness, improve identification, and prevention of healthcare-associated infections that are associated with the hospital environment.

Discovery of Tetrahydro Tanshinone I as a Naturally Occurring Covalent Pan-Inhibitor Against Gut Microbial Bile Salt Hydrolases.

Gut microbial bile salt hydrolases (gmBSHs), an important class of bacteria-produced cysteine hydrolases, play a crucial role in bile acid metabolism. Modulating the total gmBSH activity is a feasible way for ameliorating some metabolic diseases including colorectal cancer, type 2 diabetes, and obesity. This study reported the discovery and characterization of a botanical compound as a covalent pan-inhibitor of gmBSHs. Following the screening of more than 100 botanical compounds, tanshinones were found with strong time-dependent anti-EfBSH effects. After that, a total of 17 naturally occurring tanshinones were collected, and their anti-EfBSH potentials were tested. Among all tested tanshinones, tetrahydro tanshinone I (THTI) exhibited the most potent inhibitory effects against five gmBSHs (EfBSH, LsBSH, BtBSH, CpBSH, and BlBSH), showing the IC50 values ranging from 0.28 ± 0.05 µM to 1.62 ± 0.07 µM. Further investigations showed that THTI could covalently modify the conserved catalytic cysteine (Cys2) of all tested gmBSHs, while this agent could strongly inhibit the total gmBSHs activity in live microorganisms and murine gut luminal content. Collectively, THTI is identified as a naturally occurring covalent pan-inhibitor of gmBSHs, which offers a promising lead compound to develop more efficacious gmBSHs inhibitors for the management of bile acid metabolism and related metabolic disorders.