Potential Biomarker Of Poor Prognosis Research Articles

Investigation the Role of Calcium and Vitamin D3 And Some Biochemical Parameters in Patients with Renal Failure of Renal Failure

Coronavirus Disease 2019 is a primarily respiratory illness that can cause thrombotic disorders. Elevation of D-dimer is a potential biomarker for poor prognosis in COVID-19, though optimal cutoff value for D-dimer to predict mortality has not yet been established. This study aims to assess the accuracy of admission D-dimer in the prognosis of COVID-19 and to establish the optimal cutoff D-dimer value to predict hospital mortality. Clinical and laboratory parameters and outcomes of confirmed COVID-19 cases admitted to four hospitals in Kathmandu were retrospectively analyzed. Admitted COVID-19 cases with recorded D-dimer and definitive outcomes were included consecutively. D-dimer was measured using immunofluorescence assay and reported in Fibrinogen Equivalent Unit (μg/ml). The receiver operating characteristic curve was used to determine the accuracy of D-dimer in predicting mortality, and to calculate the optimal cutoff value, based on which patients were divided into two groups and predictive value of D-dimer for mortality was measured. D-dimer levels were higher in COVID-19 patients and were related with markers of inflammation, and after treatments, D-dimer levels decreased which was synchronous with hsCRP levels in patients with good clinical prognosis. Also, the low correlation between Padua VTE score and D-dimer levels weakened the role of D-dimer in the prediction of thrombosis.The abnormal changes of D-dimer and inflammatory factors suggest that aggressive anticoagulant therapy might be needed.

The clinicopathological and prognostic significance of PSMD14 in cancers based on bioinformatics and meta-analysis.

Aim: To evaluate the clinic-pathological features and prognostic value regarding PSMD14 in cancers.Materials & methods: Literature was gathered from public databases until 22June2023 to analyze data on survival rates and clinicopathological characteristics associated with PSMD14. TCGA and GEO data were also utilized for validation.Results: Eight reports on seven types of tumors showed that high PSMD14 expression was linked to poorer overall survival and disease-free survival. PSMD14 expression also correlated with larger tumor size, differentiationand metastasis, as well as the effectiveness of various chemotherapy drugs.Conclusion: PSMD14 could serve as a potential biomarker of poor prognosis in cancers, including lung cancer, head and neck squamous cell carcinoma, ovarian cancer, breast cancer and hepatocellular carcinoma.

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.

ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.

Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.

Comprehensive analysis of EphA2 in pan-cancer: A prognostic biomarker associated with cancer immunity.

Several studies have reported a significant relationship between Ephrin receptor A2 (EphA2) and malignant progression in numerous cancers. However, there is a lack of comprehensive pan-cancer analysis on the prognostic value, mutation status, methylation landscape, and potential immunological function of EphA2. Using The Cancer Genome Atlas, Genotype Tissue Expression Database and GEO data, we analysed the differences in EphA2 expression between normal and tumour tissues and the effects of EphA2 on the prognosis of different tumours. Furthermore, using GSCALite, cBioPortal, TISDB, ULCLAN and TIMER 2.0 databases or platforms, we comprehensively analysed the potential oncogenic mechanisms or manifestations of EphA2 in 33 different tumour types, including tumour mutation status, DNA methylation status and immune cell infiltration. The correlation of EphA2 with immune checkpoints, tumour mutational burden, DNA microsatellite instability and DNA repair genes was also calculated. Finally, the effects of EphA2 inhibitors on the proliferation of human glioma and lung cancer cells were verified in cellular experiments. EphA2 is differentially expressed in different tumours, and patients with overexpression have poorer overall survival. In addition, gene mutations, gene copy number variation and DNA/RNA methylation of EphA2 have been identified in various tumours. Moreover, EphA2 is positively associated with immune infiltration involving macrophages and CD8+ T cells. Further, EphA2 mRNA expression is significantly associated with immune checkpoint in various cancers, especially programmed death-ligand 1. Finally, the EphA2 inhibitor ALW-II-41-27 shows potent anti-tumour activity. Our first pan-cancer study of EphA2 provides insight into the prognostic and immunological roles of EphA2 in different tumours, suggesting that EphA2 might be a potential biomarker for poor prognosis and immune infiltration in cancer.

Patient-reported symptom interference with activity- and mood-related functioning prior to start of an early-phase oncology combination trial including immune checkpoint blockade.

12084 Background: We examined symptom interference with activity- and mood-related functioning at baseline in early-stage trials of combination treatments that included at least one immune checkpoint inhibitor, and its association with quality of life (QOL)-, clinical-, and trial-related factors. Methods: Patients scheduled to begin an early-phase trial of a combination treatment with immune checkpoint blockade, and who had not received trial-related treatment were recruited into a prospective longitudinal study design (NCI R01CA242565), and completed the following validated patient-reported outcome (PRO) measures prior to trial start: MD Anderson Symptom Inventory- Immunotherapy (score range: 0-10, higher scores = worse symptom interference); NCI’s PRO Common Terminology Criteria for Adverse Events (0-4, higher = worse severity); EuroQoL-5 dimensions assessing health status (0-100, higher = better health) and problems with self-care, and the Sloan Global QOL scale (0-10, higher = better QOL). Statistical tests included Spearman’s correlation rho (r) and multivariable linear regression. Results: 977 baseline PRO measures were completed by 247 patients (median age = 59 y; 46% female). Worst symptom-related interference was with activity (3.0 on a 0-10 scale), work (2.9), and enjoyment of life (2.4). Composite score means were 2.8 for symptom interference with walking, activity, and work (WAW; activity-related functioning), and 2.1 for interference with relationships, enjoyment of life, and mood (REM; mood-related functioning). Symptoms most associated with worse WAW were fatigue (P<0.001) and appetite loss (P=0.001). Worse WAW was linked to worse REM (r=0.78, P<0.001). Diminished sexual interest/mood (DSI) was associated with worse WAW (r=0.35, P<0.001) and REM (r=0.33, P<0.001). Worse WAW was linked to shorter trial duration (P=0.003) and worse response (progression of disease/immune-related progression) on the clinical trial (P=0.05). Conclusions: This first, comprehensive and prospective examination of symptom interference with functioning at trial baseline found that worse symptom interference was linked to worse QOL, poorer clinical outcomes, and shorter trial duration. These findings suggest that baseline patient-reported symptom interference with functioning can serve as a potential biomarker of poor prognosis in investigational trials, and that trial patients may benefit from initiation of supportive care prior to trial start. [Table: see text]

Downregulation of DIP2B as a prognostic marker inhibited cancer proliferation and migration and was associated with immune infiltration in lung adenocarcinoma via CCND1 and MMP2

BackgroundDIP2B is related to cancer progression. This study investigated the roles and pathways of DIP2B in lung adenocarcinoma (LUAD). MethodsDIP2B expression and the relationship between survival time of cancer patients and DIP2B expression were analyzed. The relationship between DIP2B expression and survival time in LUAD patients was evaluated by a meta-analysis. Cox and survival analyses were used to evaluate the prognostic factors and construct a prognostic nomogram. The mechanisms and effects of DIP2B and the relationship between DIP2B expression and the immune microenvironment were investigated using bioinformatics, CCK-8, western blotting, and transwell experiments. ResultsDIP2B was overexpressed in LUAD tissues. DIP2B overexpression was associated with shorter prognosis and was an unfavorable risk factor for prognosis in LUAD patients. DIP2B co-expressed genes were involved in cell division, DNA repair, cell cycle, and others. Inhibition of DIP2B expression could downregulate the proliferation, migration, and invasion of LUAD A549 and H1299 cells, which was related to the decrease in CCND1 and MMP2 protein expression. BRCA1 overexpression was associated with short prognosis, and the nomogram formed by DIP2B and BRCA1 was associated with a poor prognosis in LUAD patients. DIP2B expression correlated with immune cells (such as CD8 T cells, Tcm, and iDCs) and cell markers. ConclusionDIP2B is a potential biomarker of poor prognosis and the immune microenvironment in LUAD. Inhibition of DIP2B expression downregulated cancer cell proliferation, migration, and invasion, which might be related to the decrease in CCND1 and MMP2 protein expression. DIP2B-related nomograms might be useful tools for predicting the prognosis of LUAD patients.

EVA1A, a novel and promising prognostic biomarker in colorectal cancer.

The purpose of this study was to investigate the potential of EVA1A as a prognostic biomarker for Colorectal cancer (CRC). The study utilized public databases to analyze the difference in Evala mRNA expression between CRC tumor tissues and adjacent normal tissues. Additionallymunohistochemical staining was performed on 90 paired tissue samples to detect EVA1A expression. The relationship between EVA1A and clinicopathological features was examined, and a Kaplan-Meier survival analysis was conducted. Univariate and multivariate Cox analyses were employed to identify prognostic factors affecting the overall survival (OS) of CRC patients. The analysis revealed a significant increase in Evala mRNA expression in CRC tumor cells compared to normal controls from public databases (P< 0.05). Immunohistochemical staining further confirmed a significant upregulation of EVA1A expression in CRC tissues (P< 0.05). High EVA1A expression was associated with age, pathological M stage, total tumor stage, and Carbohydrate antigen CA19-9 (CA19-9). Kaplan-Meier analysis demonstrated a significant association between high EVA1A expression and poor OS. Univariate and multivariate analysis identified EVA1A as an independent risk factor for CRC prognosis. The study suggests that EVA1A is increased in CRC tumor tissues and may serve as a potential biomarker for poor prognosis in CRC.

Upregulation of TTK expression is associated with poor prognosis and immune infiltration in endometrial cancer patients

BackgroundThreonine and tyrosine kinase (TTK) is associated with invasion and metastasis in various tumors. However, the prognostic importance of TTK and its correlation with immune infiltration in endometrial cancer (EC) remain unclear.MethodsThe expression profile of TTK was analyzed using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteome Cancer Analysis Consortium (CPTAC). TTK protein and mRNA levels were verified in EC cell lines. Receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of TTK to distinguish between normal and EC tissues. K-M survival analysis was also conducted to evaluate the impact of TTK on survival outcomes. Protein‒protein interaction (PPI) networks associated with TTK were explored using the STRING database. Functional enrichment analysis was performed to elucidate the biological functions of TTK. TTK mRNA expression and immune infiltration correlations were examined using the Tumor Immune Estimation Resource (TIMER) and the Tumor-Immune System Interaction Database (TISIDB).ResultsTTK expression was significantly greater in EC tissues than in adjacent normal tissues. Higher TTK mRNA expression was associated with tumor metastasis and advanced TNM stage. The protein and mRNA expression of TTK was significantly greater in tumor cell lines than in normal endometrial cell lines. ROC curve analysis revealed high accuracy (94.862%), sensitivity (95.652%), and specificity (94.894%) of TTK in differentiating EC from normal tissues. K-M survival analysis demonstrated that patients with high TTK expression had worse overall survival (OS) and disease-free survival (DFS) rates. Correlation analysis revealed that TTK mRNA expression was correlated with B cells and neutrophils.ConclusionTTK upregulation is significantly associated with poor survival outcomes and immune infiltration in patients with EC. TTK can serve as a potential biomarker for poor prognosis and a promising immunotherapy target in EC. Further investigation of the role of TTK in EC may provide valuable insights for therapeutic interventions and personalized treatment strategies.

Potential Role of MAP3K14 in Hepatocellular Carcinoma: A Study Based on Comprehensive Bioinformatical Analysis and Validation.

According to reports, MAP3K14 is considered an oncogene and is aberrantly expressed in various types of tumor cells. Its abnormal expression is closely associated with the occurrence and progression of various cancers. MAP3K14 also plays a significant role in the development of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma and its connection to tumor stem cells. The prognostic value of MAP3K14 in HCC, as well as its potential functions and roles, requires further elucidation. We evaluated the potential role of MAP3K14 in HCC based on data mining from a range of public databases. The bioinformatics analysis of TCGA, GEO, TIMER, cBioportal, Kaplan-Meier plotter, MethSurv, ENCORI and CellMiner databases was carried out. The expression of MAP3K14 protein in HCC was detected by immunohistochemical method. The mRNA and protein expression levels of MAP3K14 in tumor tissues were higher than those in normal tissues (p < 0.05). The expression of MAP3K14 was correlated with Pathologic T stage (p=0.026), Pathologic stage (p=0.032), Tumor status (p=0.024) and AFP (p=0.002). HCC patients with high expression of MAP3K14 had poor overall survival (OS), progression free survival (PFS) and recurrence free survival (RFS). Multivariate Cox regression analysis showed that the Pathologic stage (p < 0.001) and MAP3K14 expression levels (p < 0.05) is an independent prognostic factor affecting the survival of patients with liver cancer. GO/KEGG analysis suggested that key biological processes (PI3K-Akt signaling pathway) may be the mechanism promoting HCC development. In addition, MAP3K14 was significantly correlated with the infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (p < 0.05). MAP3K14 is up-regulated in HCC and is closely related to the prognosis of HCC patients. MAP3K14 may serve as a potential biomarker for poor prognosis of HCC.

A comprehensive analysis of essential meiotic endonuclease 1 to prognosis and immune infiltration in kidney renal clear cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer, and its molecular pathogenesis is unclear. In this study, we investigated the prognostic value of essential meiotic endonuclease 1 (EME1) in kidney renal clear cell carcinoma (KIRC). We downloaded the RNA-Seq expression of 526 KIRC tissues and 72 normal tissues from the TCGA database and the corresponding clinical data. The gene expression profiles associated with four clear cell renal cell carcinomas were downloaded from the GEO database for analysis. The expression of EME1 in clear renal cell carcinoma and its correlation with the clinical baseline data were analyzed. Kaplan-Meier survival curve analysis was performed to assess the relationship between EME1 and patient survival. Enrichment analysis was performed to elucidate the possible functions of EME1. We also analyzed the relationship between the EME1 expression and immune infiltration through TIMER2.0 and TISIDB online databases as well as the relationship between EME1 and common immune checkpoints. EME1 was identified as a risk factor for overall survival in clear cell renal cell carcinoma with a hazard ratio of 3.201 (95% confidence interval: 2.430-4.215; p < 0.001). EME1 was highly expressed in KIRC compared to that in normal tissues (p < 0.001) and in the worse TNM stages and late stages (stage 3/4) (p < 0.001). High EME1 expression was strongly associated with the advanced T stage (p = 0.003), advanced N stage (p = 0.002), and advanced M stage (p = 0.006). Research data on KIRC were simultaneously collected and analyzed from the GEO database, including GSE40435, GSE53000, GSE68417, and GSE53757. EME1 predicted the survival status in KIRC patients (AUC = 0.62). We further established a nomogram including the correlation between the high and low EME1 expression, and EME1 was found to contribute to the prediction of the probability of patient survival with a c-index = 0.796. Kaplan-Meier analysis revealed a lower likelihood of survival with a high EME1 expression (p < 0.001). In addition, further bioinformatics analysis suggested that EME1 may be associated with the extent of immune infiltration in KIRC. An increased expression of EME1 in KIRC is thus associated with advanced clinicopathological features, possibly acting as a potential biomarker of poor prognosis in KIRC.

PTERT C250T mutation: A potential biomarker of poor prognosis in metastatic melanoma

Melanoma is the most aggressive form of skin cancer and the leading cause of death from cutaneous tumors. Several studies have associated alterations in the TERT promoter region (pTERT) with gene overexpression, aggressiveness and poor prognosis of the disease. The aim of this study was to clarify the role of pTERT molecular status in paired samples of primary melanoma and metastasis using tissue and plasma to establish a correlation with disease progression and survival.A total of 88 FFPE tissue samples from 53 patients with advanced melanoma were analyzed. Of these, 35 had paired samples. We also examined cfDNA samples from plasma of 25 patients. We detected a good correlation between primary tumors and metastases in pTERT mutation and methylation status. We were also able to identify pTERT mutations in plasma samples that correlated with mutational status in tissue samples. Interestingly, the C250T mutation was associated with worse survival and higher TERT mRNA expression, compared to the other most common mutation: C228T. In addition, hyper-methylation of the promoter region seems to be related to the progression of pTERT wild type (WT) patients. These results suggest that TERT gene alterations plays an important role during tumor progression, with the detection of the C250T mutation in tissue and plasma as a potential biomarker of poor prognosis in patients with advanced melanoma.

Tissue cadherin 17 (CDH17): A favorable prognostic determinant of colorectal cancer using digital image analysis.

e14651 Background: Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-death globally. The identification of robust prognostic markers for risk stratification of CRC would facilitate the accurate selection of high-risk patients for adjuvant therapies, hence improving patients’ survival and quality of living. Cadherin 17 (CDH17) is a validated biomarker for CRC characterized by its overexpression in tumor tissues (Zheng et al., 2021). CDH17 expression in tissue samples can be reliably detected by immunohistochemistry (IHC), which could potentially provide useful information for malignancy monitoring and prognosis. Nevertheless, the implementation of IHC in clinical settings is hindered by the lack of standardized guidelines. In this regard, the present study employed a standardized automated IHC platform and a digitalized sample scoring system to investigate CDH17 tissue expression and examine its clinical prognostic value in CRC. Methods: IHC was performed to assess CDH17 expression on paired tumor and adjacent non-tumor tissues from a cohort of 198 retrospective CRC cases, using the Lic3 antibody and an automated IHC system integrated with AI-digital imaging analysis. The M-score was generated for CDH17 membrane staining according to the formula (1 × % of weakly stained cells + 2 × % moderately stained cells + 3 × % of strongly stained cells)/6. Clinical correlation analysis with TNM, differentiation, and metastasis was determined. The prognostic value of tissue CDH17 was evaluated by Kaplan-Meier curves and Cox regression analyses on patients’ OS and RFS. Comparison of M-score and pathologist visual scoring was made to assess the validity of software-derived IHC scoring. Results: A significantly higher tissue CDH17 level was observed in CRC patients with advanced tumour staging (Early vs. Late stage, p = 0.0493; Mann-Whitney U test) and distant metastasis (p = 0.0188; Mann-Whitney U test). CRC patients with high M-score (M-ScoreHigh; cut-off = 30) were associated with poorer OS and shorter RFS (OS, p = 0.015; RFS, p = 0.018; Log-rank test). Subgroup analysis revealed that M-ScoreHigh in early-stage CRC predicts patients’ disease recurrence of less than 2 years after curative surgery (p = 0.025; Log rank test). Multivariate cox regression analysis showed that CDH17 was an independent prognostic factor for OS (HR = 1.918, 95% CI = 1.001-3.676, p = 0.05). A comparison of software-derived CDH17 M-score with pathologist scoring demonstrated good correlation of 0.7257 (p &lt; 0.0001, n = 36; Pearson correlation). Conclusions: The present study suggests that CDH17 is a potential biomarker of poor prognosis for CRC. Quantification of tissue CDH17 level using a standardized automated IHC platform and digital image analysis could aid in patient stratification which allows efficient treatment strategies for better survival outcomes.

Down-regulation of S1PR2 is correlated with poor prognosis and immune infiltrates in cervical squamous cell carcinoma and endocervical adenocarcinoma.

Objectives: Cervical squamous cell carcinoma and cervical adenocarcinoma (CESC) are the second leading cause of deaths from malignant tumors in women, while their therapeutic and diagnostic aims are still finited. A growing body of evidence indicated that sphingosine-1-phosphate receptor 2 (S1PR2) plays essential roles in the occurrence and development about several human cancers. Nevertheless, the key mechanism and role mechanism of S1PR2 in CESC are still unclear.Methods: We first used Tissue Expression (GTEx) and Genotypic Cancer Genome Atlas (TCGA) data to perform pan-cancer analysis on the expression and prognosis of S1PR2, and found that S1PR2 may have a potential impact on CESC. To generate a protein-protein interaction (PPI) network using the STRING database. The clusterProfiler package is used for feature-rich analysis. The Tumor IMmune Estimation Resource was used to determine the connection between S1PR2 mRNA expression and immune infiltrates. Results: S1PR2 expression in CESC tissues was down-regulated compared with adjacent normal tissues. Kaplan-Meier analysis indicated that compared with patients with high expression of S1PR2, CESC patients with low S1PR2 expression had a worse prognosis. Reduced S1PR2 expression is associated with patients with high clinical stage, more histological types of squamous cell carcinoma, and poor primary treatment outcomes. The receiver operating characteristic curve of S1PR2 was 0.870. Correlation analysis showed that the mRNA expression of S1PR2 was related to immune infiltrates and tumor purity.Conclusion: Down-regulated S1PR2 expression is related to poor survival and immune infiltration in CESC. S1PR2 is a potential biomarker for poor prognosis and as a potential target for CESC immune therapy.

The Bacterial Chaperone High-Temperature Protein G (HtpG) Decreases in Abundance with Induction Therapy in Children with Acute Lymphoblastic Leukemia

Introduction: Heat shock proteins (HSPs) are ancient and highly conserved genes that participate in protein quality control in eukaryotes and bacteria. These proteins are produced in large quantities when cells are exposed to stress that causes denaturation of essential proteins. HSPs help maintain cellular homeostasis, and act as molecular chaperones, assisting with protein folding and stability, multi-protein assembly, intracellular protein trafficking and degrading damaged proteins. The Hsp90 family of proteins includes 4 genes, with 1 (HtpG) being a bacterial form. Members of the Hsp90 family interact with a diverse set of client proteins, some involved in cell signalling and proliferation. Many of these client proteins are involved in growth, survival and adaptation of cancer cells. Eukaryotic Hsp90 plays an important role in tumorigenesis and there has been much research into the use of Hsp90 inhibitors to inhibit growth of cancer cells, but little has been done to examine what role the other paralogues have in stabilizing cancer cells. In addition, no work to date has looked at whether bacterial HtpG paralogues might interact with cancer cells. While it is anticipated that bacterial stress and the behaviour of HtpG would correlate to the host response to stress, this has not been examined. The first step is to examine bacterial HtpG gene levels before and during induction to determine if there are changes in HtpG gene abundance. Methods: Forty-eight stool samples were collected from 29 pediatric patients with Acute Lymphoblastic Leukemia (ALL) being treated at the IWK health centre, Nova Scotia, Canada after informed consent. DNA was extracted and whole shotgun metagenome sequencing (Illumina, Nextera XT) was performed. Low quality and contaminated sequences (human and PhiX174) were removed using the kneaddata pipeline (Trimmomatic and Bowtie2). Paired cleaned sequences were concatenated and HUMAnN3 was used to assign gene families to reads using the Uniref90 database. Genes assigned to HtpG or "Hsp90-like" gene families were included and summed from each sample and corrected for sequencing depth. Samples were grouped by phase of treatment (13 pre-treatment samples from 13 patients and 35 induction samples from 23 patients) for analysis. Comparisons between pre-treatment (PT) and induction (IN) samples were performed using Wilcoxon-Mann-Whitney U. Fisher's exact test was used to compare age group and sex between PT and IN samples. The study was approved by the IWK ethics board. Results: Neither sex nor age category differed between PT and IN (p=1). HtpG gene counts among the 48 stool samples from 29 patients ranged from 0 to 329 (mean 119). The mean counts of HtpG genes were significantly decreased in samples during induction therapy compared to pre-treatment (p=0.002). Shannon diversity, a measure of microbial diversity, did not differ between PT and IN samples (p=0.2793), nor did counts of bacteria (Chao-1 p=0.47). Discussion: Studies have found that Hsp90 is generally over expressed in cancer patients with elevated levels, suggesting poorer overall survival. They have been proposed as a potential biomarker of poor prognosis. We had anticipated increased stress and protein damage to occur in the gut environment as a result of chemotherapy, rather than as a result of the underlying cancer. The anticipated increase in HtpG during induction did not occur but rather declined with cancer remission. One possibility is that the decline in HtpG genes was a result of a loss of bacterial diversity due to treatment. However, we did not see significant differences in diversity between PT and IN. The increase in HtpG genes during PT and reduction during induction therapy seems to follow a similar pattern to Hsp90 expression in host cells, suggesting that bacterial HtpG might also serve as a marker of disease remission. It also highlights that a better understanding of bacterial HtpG, a protein known to be present in outer membrane vesicles, which are crucial for host communication and have been implicated in contributing to carcinogenic potential is warranted. Conclusion: This study suggests that the bacterial chaperone HtpG is possibly related to degree of inflammation caused by leukemic cells rather than leukemia treatment. A larger study is needed to verify the potential of HtpG as a marker of cancer remission or treatment toxicity or cancer immune response.

SLC11A1 associated with tumor microenvironment is a potential biomarker of prognosis and immunotherapy efficacy for colorectal cancer.

Colorectal cancer (CRC) is one of the most lethal cancers of the digestive system. The tumor microenvironment (TME) plays a central role in the initiation and development of CRC. However, little is known about the modulation mechanism of the TME in CRC. In our study, we attempted to identify a biomarker related to the TME modulation that could serve as a potential prognostic biomarker for CRC. We identified differentially expressed genes between the ImmuneScore high/low and StromalScore high/low groups. Using univariate COX regression analysis and hub gene analysis (cytoHubba), SLC11A1 was identified as the only candidate gene for subsequent analysis. CIBERSORT, EPIC, MCPcounter, and immunogenic cell death were performed to evaluate the effect of SLC11A1 on the TME. We also collected samples and performed Real-time quantitative PCR to verify the expression levels of SLC11A1 in CRC and adjacent normal tissues. The IMvigor210 cohort, TIDE score, and immunophenoscore (IPS) were used to analyze the association between SLC11A1 and immunotherapy efficacy. SLC11A1 was highly expressed in CRC tissues compared with its expression in normal colorectal tissues and was associated with poor prognosis and advanced clinicopathological stages. Gene set enrichment analysis showed that TGF-β pathways, JAK-STAT pathways, and angiogenesis were significantly enriched in the high-SLC11A1 group. Single-cell analysis validated the correlation between SLC11A1 and the TME. Using CIBERSORT, EPIC, and MCPcounter algorithms, we found that there was more macrophage and fibroblast infiltration in the SLC11A1 high-expression group. Meanwhile, high-SLC11A1 patients had lower IPS scores, higher TIDE scores, and fewer immunotherapy benefits than those of low-SLC11A1 patients. In conclusion, SLC11A1 plays a crucial role in the TME and could serve as a potential biomarker for poor prognosis and immunotherapy efficacy in CRC.

H3F3A K27M Mutation Promotes the Infiltrative Growth of High-Grade Glioma in Adults by Activating β-Catenin/USP1 Signaling.

Simple SummaryGliomas is a primary type of tumor in the central nervous system. High-grade glioma is a malignant cancerous disease and grows rapidly. This study reports the expression of H3.3K27M in high-grade glioma tissues and the association with malignant glioma cell behavior. Moreover, the results suggested that a high expression of H3.3K27M promotes the migration and invasion of glioma cells, leading to a poor prognosis by promoting the infiltration of glioma through aggravating aberrant activation of β-catenin signaling-driven pathway. H3F3A K27M (H3.3K27M) is a newly identified molecular pathological marker in glioma and is strongly correlated with the malignancy of diffuse intrinsic pontine glioma (DIPG). In recent years, accumulating evidence has revealed that other types of glioma also contain the H3.3K27M mutation. However, the role of H3.3K27M in high-grade adult glioma, the most malignant glioma, has not been investigated. In this study, we focused on exploring the expression and function of H3.3K27M in high-grade glioma in adults. We found that H3.3K27M was highly expressed at high levels in some high-grade glioma tissues. Then, we introduced H3.3K27M into H3.3 wild-type glioma cells, U87 cells and LN229 cells. We found that H3.3K27M did not affect the growth of glioma cells in vitro and in vivo; however, the survival of mice with transplanted tumors was significantly reduced. Further investigation revealed that H3.3K27M expression mainly promoted the migration and invasion of glioma cells. Moreover, we confirmed that H3.3K27M overexpression increased the levels of the β-catenin and p-β-catenin (Ser675) proteins, the ubiquitin-specific protease 1 (USP1) mRNA and protein levels, and the enhancer of zeste homolog 2 (EZH2) protein level. In addition, the β-catenin inhibitor XAV-939 significantly attenuated the upregulation of the aforementioned proteins and inhibited the increased migration and invasion caused by the H3.3K27M mutation. Overall, the H3.3K27M mutation in high-grade glioma is a potential biomarker for poor prognosis mainly due to the infiltration of glioma cells that is at least partially mediated by the β-catenin/USP1/EZH2 pathway.

RAB6B is a potential prognostic marker and correlated with the remolding of tumor immune microenvironment in hepatocellular carcinoma.

Backgrounds: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of death among all cancers. The Ras-associated binding (Rab) proteins constitute the largest family of the Ras superfamily of small GTPases, which mainly mediate membrane trafficking processes. RAB6B is a member of Rab GTPases, and it has been found to be dysregulated in various tumors. However, the clinical significance, correlations with immune cells, and stroma infiltration of RAB6B in HCC remain unclear. Methods: RAB6B mRNA and protein expression in HCC were examined using the TIMER, HCCDB, UALCAN, and HPA databases. The genetic alterations of RAB6B were analyzed by cBioPortal and COSMIC databases. The correlations between RAB6B and tumor-infiltrating immune cells and cancer-associated fibroblasts were explored by using TIMER, TISIDB, and GEPIA databases. Co-expression networks of RAB6B were investigated based on LinkedOmics. Drug sensitivity was analyzed through the GDSC and CTRP databases. RAB6B was knocked down with siRNA in HCC cell lines. EdU assay was performed to detect the cell proliferation ability, flow cytometry was used to compare the differences in the ability of apoptosis, and MTT was used to evaluate the drug sensitivity in vitro. Results: RAB6B mRNA and protein expression were upregulated in the HCC tissues. Kaplan–Meier and Cox regression analyses suggested that highly expressed RAB6B was an independent prognostic factor for poor survival in HCC patients. Moreover, we found that RAB6B expression was positively correlated with the infiltration of immune cells in HCC, including some immunosuppressive cells, chemokines, and receptors, meanwhile RAB6B expression was associated with CD8+T cells exhaustion, resulting in an immunosuppressive microenvironment. Additionally, functional enrichment analysis indicated that RAB6B may be involved in ECM remodeling in the TME, and RAB6B expression was positively associated with CAFs infiltration. Furthermore, RAB6B presented a positive association with sensitivity to GDSC and CTRP drugs. RAB6B knockdown inhibited the cell proliferation and promoted apoptosis and sensitivity to cisplatin of HCC cells in vitro. Conclusion: Our study revealed that RAB6B is a potential biomarker for poor prognosis in HCC patients and correlates with the formation of the immunosuppressive microenvironment in HCC.

Prognostic Implication and Immunological Role of PSMD2 in Lung Adenocarcinoma.

Background: Although previous studies reported that 26S proteasome non-ATPase regulatory subunit 2 (PSMD2) is involved in many human cancers. However, its clinical significance and function in lung adenocarcinoma remain unclear. Here, we examined the prognostic and immunological role of PSMD2 in lung adenocarcinoma. Methods: The Cancer Genome Atlas (TCGA) was conducted to analyze PSMD2 expression and verified using UALCAN. PrognoScan and Kaplan-Meier curves were utilized to assess the effect of PSMD2 on survival. cBioPortal database was conducted to identify the mutation characteristics of PSMD2. Functional enrichment was performed to determine PSMD2-related function. Cancer Single-cell State Atlas (CancerSEA) was used to explore the cancer functional status of PSMD2 at single-cell resolution. PSMD2-related immune infiltration analysis was conducted. Tumor-Immune system interaction database (TISIDB) was performed to verify the correlation between PSMD2 expression and tumor-infiltrating lymphocytes (TILs). Results: Both mRNA and protein expression of PSMD2 were significantly elevated in lung adenocarcinoma. High expression of PSMD2 was significantly correlated with high T stage (p = 0.014), lymph node metastases (p < 0.001), and TNM stage p = 0.005). Kaplan-Meier curves indicated that high expression of PSMD2 was correlated with poor overall survival (38.2 vs. 59.7 months, p < 0.001) and disease-specific survival (59.9 months vs. not available, p = 0.004). Multivariate analysis suggested that PSMD2 was an independent biomarker for poor overall survival (HR 1.471, 95%CI, 1.024–2.114, p = 0.037). PSMD2 had a high mutation frequency of 14% in lung adenocarcinoma. The genetic mutation of PSMD2 was also correlated with poor overall survival, disease-specific survival, and progression-free survival in lung adenocarcinoma. Functional enrichment suggested PSMD2 expression was involved in the cell cycle, RNA transport, and cellular senescence. CancerSEA analysis indicated PSMD2 expression was positively correlated with cell cycle, DNA damage, and DNA repair. Immune infiltration analysis suggested that PSMD2 expression was correlated with immune cell infiltration levels and abundance of TILs. Conclusion: The upregulation of PSMD2 is significantly correlated with poor prognosis and immune infiltration levels in lung adenocarcinoma. Our findings suggest that PSMD2 is a potential biomarker for poor prognosis and immune therapeutic target in lung adenocarcinoma.

SLC6A8 is a Potential Biomarker for Poor Prognosis in Lung Adenocarcinoma

Background: Recent studies have demonstrated that creatine can promote tumor metastasis and has implications for immune cell function. SLC6A8 encodes a membrane protein that can transport creatine inside and outside the cell. However, there are currently no studies of SLC6A8 in lung adenocarcinoma (LUAD). Methods: In this study, the expression of SLC6A8 in LUAD was analyzed using the Oncomine database, the Cancer Genome Atlas (TCGA) database, and immunohistochemical staining analysis. Survival analysis of patients with LUAD was performed using the cBioPortal and the Kaplan-Meier Plotter websites and clinical follow-up data. An analysis of the association between SLC6A8 and the tumor immune microenvironment (TIME) of LUAD was performed through the TISIDB database and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm. Then, based on the curated list of SLC6A8-related immunomodulators, three genes (NT5E, CD40LG, CD80) were selected to construct SLC6A8-related immune signatures to further evaluate the immune aspect of LUAD prognosis. Results: Our studies indicated that SLC6A8 was overexpressed in LUAD, and the high expression of SLC6A8 was associated with poor survival. Genetic alteration of SLC6A8 was also associated with a poorer prognosis. Furthermore, multivariate Cox analysis indicated that SLC6A8 could be used as an independent risk prognostic factor. Then, immune infiltration analysis indicated that SLC6A8 was also strongly associated with poor prognosis in the TIME of LUAD. A multivariate Cox proportional hazard model was then constructed, and was shown effective at identifying high-risk patients. Univariate and multivariate Cox analysis showed that the risk scoring of the model was an independent prognostic risk factor in LUAD. Conclusion: SLC6A8 may serve as a biomarker for poor prognosis in LUAD.