Multiple Clinicopathological Features Research Articles

Detection of Alternative Lengthening of Telomeres via Chromogenic In Situ Hybridization for the Prognostication of PanNETs and Other Neoplasms

Molecular studies have shown alternative lengthening to telomeres (ALT) to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A chromogenic in situ hybridization (CISH) assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multiinstitutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT–CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all P < .004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared with 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in patients with LMS and, analogous to PanNETs, a negative, independent prognostic factor. ALT–CISH was developed and validated in not only PanNETs but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.

Upregulated Nuclear Expression of Soluble Epoxide Hydrolase Predicts Poor Outcome in Breast Cancer Patients: Importance of the Digital Pathology Approach.

Breast cancer (BC) is the most common cancer in women, with incidence rates increasing globally in recent years. Therefore, it is important to find new molecules with prognostic and therapeutic value to improve therapeutic response and quality of life. The polyunsaturated fatty acids (PUFAs) metabolic pathway participates in various physiological processes, as well as in the development of malignancies. Although aberrancies in the PUFAs metabolic pathway have been implicated in carcinogenesis, the functional and clinical relevance of this pathway has not been well explored in BC. To evaluate the clinical significance of soluble epoxide hydrolase (EPHX2) expression in Mexican patients with BC using tissue microarrays (TMAs) and digital pathology (DP). Immunohistochemical analyses were performed on 11 TMAs with 267 BC samples to quantify this enzyme. Using DP, EPHX2 protein expression was evaluated solely in tumor areas. The association of EPHX2 with overall survival (OS) was detected through bioinformatic analysis in public databases and confirmed in our cohort via Cox regression analysis. Clear nuclear expression of EPHX2 was identified. Receiver operating characteristics (ROC) curves revealed the optimal cutoff point at 2.847062 × 10-3 pixels, with sensitivity of 69.2% and specificity of 67%. Stratification based on this cutoff value showed elevated EPHX2 expression in multiple clinicopathological features, including older age and nuclear grade, human epidermal growth factor receptor 2 (HER2) and triple negative breast cancer (TNBC) subtypes, and recurrence. Kaplan-Meier curves demonstrated how higher nuclear expression of EPHX2 predicts shorter OS. Consistently, multivariate analysis confirmed EPHX2 as an independent predictor of OS, with a hazard ratio (HR) of 3.483 and a 95% confidence interval of 1.804-6.724 (p < 0.001). Our study demonstrates for the first time that nuclear overexpression of EPHX2 is a predictor of poor prognosis in BC patients. The DP approach was instrumental in identifying this significant association. Our study provides valuable insights into the potential clinical utility of EPHX2 as a prognostic biomarker and therapeutic target in BC.

The tumor-stroma ratio in giant cell tumor of bone: associations with the immune microenvironment and responsiveness to denosumab treatment

BackgroundCurrently, there is limited understanding regarding the clinical significance of the tumor-stroma ratio (TSR) in giant cell tumor of bone (GCTB). Hence, we aimed to investigate the distribution of TSR in GCTB and explore its correlation with various clinicopathologic factors, immune microenvironment, survival prognosis, and denosumab treatment responsiveness.MethodsWe conducted a multicenter cohort study comprising 426 GCTB patients treated at four centers. TSR was evaluated on hematoxylin and eosin-stained and immunofluorescent sections of tumor specimens. Immunohistochemistry was performed to assess CD3+, CD4+, CD8+, CD20+, PD-1+, PD-L1+, and FoxP3+ TIL subtypes as well as Ki-67 expression levels in 426 tissue specimens. These parameters were then analyzed for their correlations with patient outcomes [local recurrence-free survival (LRFS) and overall survival (OS)], clinicopathological features, and denosumab treatment responsiveness.ResultsLow TSR was significantly associated with poor LRFS and OS in both cohorts. Furthermore, TSR was also correlated with multiple clinicopathological features, TIL subtype expression, and denosumab treatment responsiveness. TSR demonstrated similar predictive capabilities as the conventional Campanacci staging system for predicting patients' LRFS and OS.ConclusionThe results of this study provide evidence supporting the use of TSR as a reliable prognostic tool in GCTB and as a predictor of denosumab treatment responsiveness. These findings may aid in developing individualized treatment strategies for GCTB patients in the future.

Molecular subtype identification and prognosis stratification based on golgi apparatus-related genes in head and neck squamous cell carcinoma

BackgroundAbnormal dynamics of the Golgi apparatus reshape the tumor microenvironment and immune landscape, playing a crucial role in the prognosis and treatment response of cancer. This study aims to investigate the potential role of Golgi apparatus-related genes (GARGs) in the heterogeneity and prognosis of head and neck squamous cell carcinoma (HNSCC).MethodsTranscriptional data and corresponding clinical information of HNSCC were obtained from public databases for differential expression analysis, consensus clustering, survival analysis, immune infiltration analysis, immune therapy response assessment, gene set enrichment analysis, and drug sensitivity analysis. Multiple machine learning algorithms were employed to construct a prognostic model based on GARGs. A nomogram was used to integrate and visualize the multi-gene model with clinical pathological features.ResultsA total of 321 GARGs that were differentially expressed were identified, out of which 69 were associated with the prognosis of HNSCC. Based on these prognostic genes, two molecular subtypes of HNSCC were identified, which showed significant differences in prognosis. Additionally, a risk signature consisting of 28 GARGs was constructed and demonstrated good performance for assessing the prognosis of HNSCC. This signature divided HNSCC into the high-risk and low-risk groups with significant differences in multiple clinicopathological characteristics, including survival outcome, grade, T stage, chemotherapy. Immune response-related pathways were significantly activated in the high-risk group with better prognosis. There were significant differences in chemotherapy drug sensitivity and immune therapy response between the high-risk and low-risk groups, with the low-risk group being more suitable for receiving immunotherapy. Riskscore, age, grade, and radiotherapy were independent prognostic factors for HNSCC and were used to construct a nomogram, which had good clinical applicability.ConclusionsWe successfully identified molecular subtypes and prognostic signature of HNSCC that are derived from GARGs, which can be used for the assessment of HNSCC prognosis and treatment responses.

Next-generation sequencing-based analysis of homologous recombination repair gene variant in ovarian cancer

BackgroundOvarian cancer is the leading cause of death from gynecological malignancies. Investigating the HRR-related gene status, notably BRCA1/2 in different regions and populations is of great significance for formulating accurate target therapy. MethodsWe collected 124 ovarian cancer cases from the Affiliated Hospital of.Qingdao University, detected the genomic alteration of 32 genes by NGS, including.19 HRR-related genes, 9 proto-oncogenes and 4 tumor suppressor genes. Clinicopathological characteristics, variants, clinical significance, and correlation with prognosis were analyzed. ResultsThe incidence of HRR-related gene mutation was 59.68 % and no statistical significance was found with multiple clinicopathological characteristics. BRCA1/2 (27.42 %) were the most frequent mutated HRR genes. 23 (18.55 %) cases harbored gBRCA1/2 mutation, with all BRCA1 mutations were pathogenic/likely pathogenic and 2 cases of BRCA2 mutation was variant of uncertain significance. Somatic BRCA1/2 mutations were found in 12 (9.68 %) cases, and sBRCA1/2 had a higher frequency in less common ovarian cancer than high-grade serous carcinoma. HRR-related gene mutation status was associated with better prognosis than HRR wild-type. ConclusionsSomatic BRCA1/2 mutation has higher incidence in less common ovarian cancer. HRR gene mutation status is an independent prognosis factor in ovarian cancer. Clarifying the HRR gene status is important for the selection of target therapy as well as the evaluation of prognosis.

Construction of gastric cancer prognostic signature based on the E26 transcription factor and the identification of novel oncogene ELK3.

The aim of the present study was to investigate the function of 29 E26 (ETS) transcription factor families in gastric cancer (GC) and determine their association with prognosis. Our analysis of the expression of the ETS family revealed that 28 genes were dysregulated in GC, and that their expression was associated with multiple clinicopathological features (P<0.05). Based on the expression signature of the ETS family, consensus clustering was performed to generate two gastric cancer subtypes. These subtypes exhibited differences in overall survival (OS, P = 0.161), disease-free survival (DFS, P<0.05) and GC grade (P<0.01). Functional enrichment analysis of the target genes associated with the ETS family indicated that these genes primarily contribute to functions that facilitate tumor progression. A systematic statistical analysis was used to construct a prognostic model related to OS and DFS in association with the ETS family. This model demonstrated that the maximum area under the curve (AUC) values for predicting OS and DFS were 0.729 and 0.670, respectively, establishing ETS as an independent prognostic factor for GC Furthermore, a nomogram was created from the prognostic signature, and its predictive accuracy was confirmed by a calibration curve. Finally, the expression and prognostic significance of the six genes comprising the model were also examined. Among these, ELK3 was found to be significantly overexpressed in GC clinical samples. Subsequent in vitro and in vivo studies verified that ELK3 regulates GC proliferation and metastasis, highlighting its potential as a therapeutic target for gastric cancer.

CENPL accelerates cell proliferation, cell cycle, apoptosis, and glycolysis via the MEK1/2-ERK1/2 pathway in hepatocellular carcinoma

Centromere protein L (CENPL) is involved in the mitotic process of eukaryotic cells and the development of various types of cancer. However, its role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the expression and clinical significance of CENPL in HCC, and explore its involvement in regulating HCC cell proliferation, apoptosis, cell cycle, and glycolysis both in vivo and in vitro. CENPL expression was analyzed in HCC and normal liver tissues using The Cancer Genome Atlas, Gene Expression Omnibus mining, real-time quantitative polymerase chain reaction, and immunohistochemistry. Functional assays were used to assess the role of CENPL in HCC cell proliferation, apoptosis, cell cycle, and glycolysis. The potential pathways underlying the regulatory effects of CENPL, as well as the expression of mitogen-activated protein kinase (MAPK) signaling pathway-related molecules and markers of proliferation and glycolysis were investigated. CENPL was significantly upregulated in HCC tissue and associated with multiple clinicopathological features and poor patient prognosis. Univariate and multivariate analyses demonstrated that CENPL may serve as an independent prognostic factor for HCC. Upregulation of CENPL in HCC regulated tumor proliferation and glycolytic processes. Mechanistic studies revealed that differentially expressed genes between the CENPL-overexpressing and control groups were mainly concentrated in the MAPK signaling pathway. Pathway inhibition analysis indicated that CENPL activated the MEK1/2-ERK1/2 signaling pathway to promote proliferation and glycolysis in HCC cells. This study elucidated the role of CENPL in regulating cell proliferation, apoptosis, cell cycle, and glycolysis in HCC. CENPL may represent a therapeutic target and prognostic biomarker for HCC.

Construction and validation of a novel IGFBP3-related signature to predict prognosis and therapeutic decision making for Hepatocellular Carcinoma.

IGFBP3 plays a pivotal role in carcinogenesis by being anomalously expressed in some malignancies. However, the clinical value of IGFBP3 and the role of IGFBP3-related signature in HCC remain unclear. Multiple bioinformatics methods were used to determine the expression and diagnostic values of IGFBP3. The expression level of IGFBP3 was validated by RT-qPCR and IHC. A IGFBP3-related risk score (IGRS) was built via correlation analysis and LASSO Cox regression analysis. Further analyses, including functional enrichment, immune status of risk groups were analyzed, and the role of IGRS in guiding clinical treatment was also evaluated. IGFBP3 expression was significantly downregulated in HCC. IGFBP3 expression correlated with multiple clinicopathological characteristics and demonstrated a powerful diagnostic capability for HCC. In addition, a novel IGRS signature was developed in TCGA, which exhibited good performance for prognosis prediction and its role was further validated in GSE14520. In TCGA and GSE14520, Cox analysis also confirmed that the IGRS could serve as an independent prognostic factor for HCC. Moreover, a nomogram with good accuracy for predicting the survival of HCC was further formulated. Additionally, enrichment analysis showed that the high-IGRS group was enriched in cancer-related pathways and immune-related pathways. Additionally, patients with high IGRS exhibited an immunosuppressive phenotype. Therefore, patients with low IGRS scores may benefit from immunotherapy. IGFBP3 can act as a new diagnostic factor for HCC. IGRS signature represents a valuable predictive tool in the prognosis prediction and therapeutic decision making for Hepatocellular Carcinoma.

A pilot study evaluating somatic mutational burden and signatures among endometrial cancer patients: Is there prognostic benefit to whole genome sequencing?

e17629 Background: Whole genome sequencing (WGS) has emerged as a tool to characterize mutational burden and potentially identify new therapeutic targets and predictive biomarkers. In this study, we describe the mutational landscape of diverse patients with endometrial cancer using WGS and explore associations between mutations and clinicopathologic characteristics. Methods: Patients with endometrial cancer were prospectively consented and WGS was performed on tumors and blood. Using the the New York Genome Center Cancer pipeline, we identified high confidence somatic mutations in our patient cohort (identified by 2 or more variant callers). Somatic variants were categorized into mutational signatures based on the Catalog of Somatic Mutations in Cancer (COSMIC) v2. Associations between COSMIC signatures and clinicopathologic variables were evaluated using ANOVA tests. Results: Sixteen patients with endometrial cancer were enrolled; 10 (62.5%) self-identified as White, 4 (25.0%) as Black, and 2 (12.5%) as Asian. Tumor histology was endometrioid (13, 81.3%) or serous/clear cell (2, 12.5%), with both low grade (9, 56.3%) and high grade (7, 43.8%) tumors. The most frequently mutated genes were PTEN (15, 93.8%), ARID1A (9, 56.3%), PIK3CA (9, 56.3%), and TP53 (6, 37.5%). PIK3CA mutations were found in all mismatch repair (MMR) deficient tumors (5), compared to only 30.0% (3) of patients with intact MMR mechanisms (FDR p = 0.0256). Signature 3, associated with BRCA mutations and loss of DNA double-strand break-repair by homologous recombination, was enriched in p53 mutated tumors (p = 0.0036). Signature 1, associated with age, was enriched in patients with MMR intact tumors (p = 0.0475), while signatures 6 and 20, associated with defective DNA MMR and microsatellite unstable tumors, were enriched in patients with in MMR deficient tumors (p &lt; 0.0001 and p = 0.0022, respectively). Signature 8, of unknown etiology, was enriched in patients with MMR intact tumors, advanced disease (p = 0.0045), disease spread to lymph nodes (p = 0.0231), and disease recurrence (p = 0.0021). Signature 12, also of unknown etiology, was enriched in MMR deficient tumors (p = 0.0005) and stage 1 disease (p = 0.0235). Conclusions: WGS revealed distinct patterns of mutational burden associated with clinicopathologic variables. MMR status was associated with PIK3CA mutations and multiple mutational signatures. Mutational signature 8 was associated with multiple clinicopathologic characteristics associated with poor prognosis, suggesting utility as a biomarker. Further investigation regarding the mechanism of the mutational signatures and correlation with prognostic factors may shed light on disparate biologic endometrial cancer outcomes and serve as a source of hypothesis-generation for the development of targeted therapies.

Comprehensive analysis reveals TSEN54 as a robust prognosis biomarker and promising immune-related therapeutic target for hepatocellular carcinoma.

Hepatocellular carcinoma represents the most common primary malignancy of all liver cancer types and its prognosis is usually unsatisfactory. TSEN54 encodes a protein constituting a subunit of the tRNA splicing endonuclease heterotetramer. Previous researches concentrated on the contribution of TSEN54 in pontocerebellar hypoplasia, but no studies have yet reported its role in HCC. TIMER, HCCDB, GEPIA, HPA, UALCAN, MEXPRESS, SMART, TargetScan, RNAinter, miRNet, starBase, Kaplan-Meier Plotter, cBioPortal, LinkedOmics, GSEA, TISCH, TISIDB, GeneMANIA, PDB, GSCALite were applied in this research. We identified the upregulation of TSEN54 expression in HCC and related it to multiple clinicopathological features. Hypomethylation of TSEN54 was closely associated with its high expression. HCC sufferers who held high TSEN54 expression typically had shorter survival expectations. Enrichment analysis showed the involvement of TSEN54 in the cell cycle and metabolic processes. Afterward, we observed that TSEN54 expression level had a positive relationship to the infiltration level of multiple immune cells and the expression of several chemokines. We additionally identified that TSEN54 was related to the expression level of several immune checkpoints and TSEN54 was linked to several m6A-related regulators. TSEN54 is a prognostic marker of HCC. TSEN54 could become a prospective candidate for HCC diagnosis and therapy.

Abstract 1412: Co-existence of TP53 mutation confers endocrine resistance in PIK3CA-mutated ER+HER2- breast cancer

Abstract Background: PIK3CA mutation is commonly found in estrogen receptor (ER)+ human epidermal growth factor receptor-2 (HER2)- breast cancer (BC) and can be therapeutically targeted by alpelisib, an alpha-specific PIK3CA inhibitor. While previous studies presented conflicting results on the prognostic influence of PIK3CA mutation among ER+HER2- breast cancer, few have been able to address causes of the prognostic discrepancy on a clinical level. In this study, we investigated clinical and genomic features according to a coexistence of TP53 mutation in PIK3CA mutated ER+HER2- breast cancer. Methods: Tumor tissue based next generation sequencing (NGS) was analyzed for 224 HR+ HER2- BC patients from April 2017 to August 2021 in Gangnam Severance Hospital, Seoul, South Korea. Matching clinical records with patient information were reviewed retrospectively. Clinicopathologic features including age, tumor size, histologic grade (HG), TNM stage, estrogen receptor (ER) expression, progesterone (PgR) expression, Ki-67, and Oncotype Dx Recurrence Score (RS) were analyzed. Further analysis was carried out using The Cancer Genome Atlas (TCGA) to explore the relationship of mutation status with intrinsic subtype and risk of recurrence (ROR) score. Results: We identified PIK3CA mutation (PIK3CA m) in 105 (46.9%) of 224 patients, and of these, TP53 co-mutation was found in 25 (23.8%). None of clinicopathologic features were different according to PIK3CA mutation. When PIK3CA m cohort was analyzed according to TP53 mutation (TP53 m) status, tumors with TP53 m presented unfavorable features such as higher HG (p&amp;lt;0.001), lower PgR expression (TP53 wt: Median 7 versus TP53 m: Median 5, p=0.027), and higher N stage (p=0.008). It also displayed a significantly higher proliferative profiles with Ki-67 (TP53 wt: Median 15 versus TP53 m: Median 20, p&amp;lt;0.001) and Oncotype Dx RS (TP53 wt: Median 15 versus TP53 m: Median 26.5, p=0.002). In the 539 ER+HER2- breast cancer from the TCGA database, PIK3CA and TP53 co-mutation was found in 33 (6.1%). Distribution of intrinsic subtypes revealed a higher rate of Luminal B in PIK3CA and TP53 co-mutant tumors (51.5%) than in PIK3CA m and TP53 wt tumors (14.3%, p&amp;lt;0.001). The ROR score was found to be higher in the PIK3CA-TP53 co-mutation compared to PIK3CA m alone (p&amp;lt;0.001). Conclusion: Unlike PIK3CA mutation, PIK3CA and TP53 co-mutation clearly divided multiple clinicopathologic features of HR+ HER2- BC including with. Poorer prognosis of co-mutation was also corroborated by TCGA analysis of intrinsic subtype and ROR score. These findings indirectly suggest that co-mutation of TP53 gene may be associated with less sensitivity to PIK3CA targeted therapy in PIK3CA m ER+HER2- breast cancers. Further research is warranted to improve an efficacy of PIK3CA targeted therapy for PIK3CA m ER+ breast cancer with endocrine-resistant factors. Citation Format: Yoonwon Kook, Kyungsoo Kim, Ji Soo Jang, Seung Ho Baek, Soong June BAe, Joon Jeong, Sung Gwe Ahn. Co-existence of TP53 mutation confers endocrine resistance in PIK3CA-mutated ER+HER2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1412.

DICER1-associated central nervous system sarcoma: A comprehensive clinical and genomic characterization of case series of young adult patients.

DICER1 alterations are associated with intracranial tumors in the pediatric population, including pineoblastoma, pituitary blastoma, and the recently described "primary DICER1-associated CNS sarcoma" (DCS). DCS is an extremely aggressive tumor with a distinct methylation signature and a high frequency of co-occurring mutations. However, little is known about its treatment approach and the genomic changes occurring after exposure to chemoradiotherapy. We collected clinical, histological, and molecular data from eight young adults with DCS. Genomic analysis was performed by Next-generation Sequencing (NGS). Subsequently, an additional germline variants analysis was completed. In addition, an NGS analysis on post-progression tumor tissue or liquid biopsy was performed when available. Multiple clinicopathological characteristics, treatment variables, and survival outcomes were assessed. Median age was 20 years. Most lesions were supratentorial. Histology was classified as fusiform cell sarcomas (50%), undifferentiated (unclassified) sarcoma (37.5%), and chondrosarcoma (12.5%). Germline pathogenic DICER1 variants were present in two patients, 75% of cases had more than one somatic alteration in DICER1, and the most frequent commutation was TP53. Seven patients were treated with surgery, Ifosfamide, Cisplatin, and Etoposide (ICE) chemotherapy and radiotherapy. The objective response was 75%, and the median time to progression (TTP) was 14.5 months. At progression, the most common mutations were in KRAS and NF1. Overall survival was 30.8 months. DCS is an aggressive tumor with limited therapeutic options that requires a comprehensive diagnostic approach, including molecular characterization. Most cases had mutations in TP53, NF1, and PTEN, and most alterations at progression were related to MAPK, RAS and PI3K signaling pathways.

In vivo detection of circulating tumor cells predicts high-risk features in patients with bladder cancer.

Previous studies have suggested the potential diagnostic value of circulating tumor cells (CTCs). This study aims to validate the efficacy of in vivo detection of CTCs in bladder cancer (BC) patients. A total of 216 BC patients were enrolled in this study. All patients had one in vivo detection of CTCs before initial treatment as a baseline parameter. The results of CTCs were associated with different clinicopathological features including molecular subtypes. PD-L1 expression on CTCs was also assessed and compared with its expression on tumors. CTC positive was defined as > 2 CTCs detected. Among all 216 patients, 49 (23%) were detected as CTC positive (> 2 CTCs) at baseline. Positive detection of CTCs was associated with multiple high-risk clinicopathological features including the multiplicity of the tumor (P = 0.02), tumor size (P < 0.01), tumor stage (P < 0.01), tumor grade (P < 0.01) and tumor PD-L1 expression (P = 0.01). The expression of PD-L1 on tumor and CTCs were not coordinated. Only 55% (74/134) matched the same status of PD-L1 expression on tumor and CTCs, along with 56 CTC (+) Tissue (-) and 4 CTC (-) Tissue (+) (P < 0.01). Our study has demonstrated the efficacy of in vivo detection of CTCs. The positive detection of CTCs is associated with multiple clinicopathological features. PD-L1 expression on CTCs has the potential to be a supplementary biomarker for immunotherapy.

A novel risk score model based on pyroptosis-related genes for predicting survival and immunogenic landscape in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer worldwide, with high incidence and mortality. Pyroptosis, a form of inflammatory-regulated cell death, is closely associated with oncogenesis. Expression profiles of HCC were downloaded from the TCGA database and validated using the ICGC and GEO databases. Consensus clustering analysis was used to determine distinct clusters. The pyroptosis-related genes (PRGs) included in the pyroptosis-related signature were selected by univariate Cox regression and LASSO regression analysis. Kaplan-Meier and receiver operating characteristic (ROC) analyses were performed to estimate the prognostic potential of the model. The characteristics of infiltration of immune cells between different groups of HCC were explored. Two independent clusters were identified according to PRG expression. Cluster 2 showed upregulated expression, poor prognosis, increased immune cell infiltration and worse immunotherapy response than cluster 1. A prognostic risk signature consisting of five genes (GSDME, NOD1, PLCG1, NLRP6 and NLRC4) was identified. In the high-risk score group, HCC patients showed decreased survival rates. In particular, multiple clinicopathological characteristics and immune cell infiltration were significantly associated with the risk score. Notably, the 5 PRGs in the risk score have been implicated in carcinogenesis, immunological pathways and drug sensitivity. A prognostic signature comprising five PRGs can be used as a potential prognostic factor for HCC. The PRG-related signature provides an in-depth understanding of the association between pyroptosis and chemotherapy or immunotherapy for HCC patients.

PRRX1 promotes colorectal cancer stemness and chemoresistance via the JAK2/STAT3 axis by targeting IL-6

Stemness acquirement is one of the hallmarks of cancer and the major reason for the chemoresistance and poor prognosis of colorectal cancer (CRC). Previous research has revealed the stimulatory role of paired related homeobox 1 (PRRX1) on CRC metastasis. However, the role of PRRX1 in stemness acquirement and chemoresistance of CRC is still not clear. A retrospective cohort study was performed to investigate the relationship between PRRX1 expression and multiple clinicopathological characteristics of CRC patients. The functional effects of PRRX1 on stemness and chemoresistance of CRC cells were validated by in vitro and in vivo assays. Gene set enrichment analysis (GSEA) and JASPAR software were performed to predict the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA), Western blot, immunofluorescence, and dual-luciferase reporter assays were used to confirm the PRRX1-mediated signaling and its downstream factors. The expression of PRRX1 was up-regulated in CRC tissues and cell lines compared to normal epithelial tissues and cell lines. High expression of PRRX1 was tightly associated with the metastasis, chemoresistance, and poor prognosis of CRC patients. Additionally, PRRX1 significantly promoted the proliferation, viability, stemness, and chemoresistance of CRC cells, as well as the activation of the interleukin-6 (IL-6)/JAK2/STAT3 axis. Inhibiting the expression of IL-6 dramatically eliminated the effects of PRRX1 on CRC cell stemness and chemoresistance. PRRX1 plays a vital role in the stemness and chemoresistance of CRC cells via JAK2/STAT3 signaling by targeting IL-6. Further, PRRX1 may be a valid biomarker for predicting the effect of chemotherapy and prognosis of CRC patients.

Factors influencing apparent diffusion coefficient value in extrahepatic cholangiocarcinoma: A retrospective study

BackgroundMost cases of extrahepatic cholangiocarcinoma (ECC) show various degrees of hyperintensity on diffusion-weighted imaging (DWI) and hypointensity on apparent diffusion coefficient (ADC). However, the factors influencing ADC values in ECC have not yet been explored extensively. Therefore, this study explored the independent factors influencing ADC values in ECC. MethodsA total of 88 patients with ECC confirmed by surgical pathology were retrospectively assessed. All patients underwent abdominal magnetic resonance imaging (MRI) at 3.0 T and ADC values of the tumor were measured. The correlation between ADC values and multiple clinicopathological features in ECC was analyzed, and independent factors influencing the ADC values in ECC were explored further. ResultsThe ADC value of the tumor showed a significant difference in different perineural invasion group (p = 0.048), microvascular invasion group (p = 0.001), vascular endothelial growth factor expression group (p < 0.001), lymphatic status group (p = 0.003), and differentiation degree (DD) group (p < 0.001). However, there were no significant differences in different sex (p = 0.715), tumor location (p = 0.659), and degree of T stage (p = 0.879). Moreover, ADC value was negatively correlated with microvascular density (r = -0.725, p < 0.001) and lesion size (r = -0.244, p = 0.023). Nevertheless, there was no correlation between ADC value and patient age (r = 0.026, p = 0.812). Further regression analysis indicated that ADC value was independently associated with pathological DD of ECC (R2 = 0.678, p < 0.001) but not with other clinicopathological factors (p > 0.05). ConclusionADC value of ECC is independently correlated with pathological DD of ECC, indicating that ADC value is a potential imaging biomarker for predicting the degree of ECC malignancy.

Excessive IL-15 promotes cytotoxic CD4 + CD28− T cell-mediated renal injury in lupus nephritis

BackgroundPatients with systemic lupus erythematosus (SLE) are highly susceptible to infection and cardiovascular events, suggesting that chronic antigenic stimulation may accelerate premature aging in SLE patients. Premature aging in SLE is often accompanied with the expansion of cytotoxic CD4 + CD28−T cells. Damage caused by CD4 + CD28− T cells enhances the progressive aging of the tissue function and loss of organism’s fitness. The high serum level of IL-15 has been implicated in the pathogenesis of SLE, but its role in CD4 + CD28−T cell-mediated cytotoxicity in nephritic SLE remains unclear. The aim of this study was to investigate the effect of IL-15 on functional properties and associated renal damage of cytotoxic CD4 + CD28− T cell in lupus nephritis (LN).ResultsFlow cytometry showed that the number of circulating innate-like CD4 + CD28− T cells was increased in patients with nephritic SLE. Immunofluorescence showed CD4 + CD28− T cell infiltration in the kidney of LN patients, which was correlated with multiple clinicopathological features including estimated glomerular filtration rate (eGFR), proteinuria, the proportion of glomerulosclerosis and the degree of renal chronicity. In addition, a high level of IL-15 and IL15-expressing macrophage infiltration was detected in the periglomerular and intraglomerular tissues of LN patients, which enhanced the innate features, cytokine secretion and migratory capability of CD4 + CD28− T cells, and finally exerted direct TCR-independent cytotoxicity on glomerular endothelial cells in an IL-15-dependent manner in vitro.ConclusionOur study demonstrated that excessive IL-15 potentially promoted cytotoxic CD4 + CD28− T cell-mediated renal damage in LN. This finding may provide new insights into the potential association of premature aging and tissue damage in LN.

CSTF2 Acts as a Prognostic Marker Correlated with Immune Infiltration in Hepatocellular Carcinoma

BackgroundCleavage stimulation factor 2 (CSTF2) encodes a nuclear protein that is implicated in the development of various cancers. However, the role of CSTF2 in hepatocellular carcinoma (HCC) has not been understood. This study aims to explore the function of CSTF2 in HCC.MethodsThe expression, diagnostic capability, prognostic value, and immune cell effect of CSTF2 in HCC were explored using various databases. The expression level of CSTF2 were validated in our cell lines. The effect of CSTF2 on hepatocarcinogenesis was explored by CSTF2 silencing.ResultsCSTF2 expression was significantly elevated in HCC and correlated with multiple clinicopathological characteristics. CSTF2 exhibited good diagnostic capability in discriminating HCC samples from nontumorous samples. High CSTF2 expression was significantly related to poor overall survival. Univariate and multivariate Cox regression analyses suggested that CSTF2 expression was an independent risk factor for HCC. These results were validated in ICGC cohorts. In addition, the nomogram based on CSTF2 showed better predictive performance than the AJCC staging system in TCGA and ICGC cohorts. Functional enrichment analysis revealed that CSTF2-related genes were involved in DNA/RNA processing and the cell cycle. In addition, we found that CSTF2 expression was closely related to the levels of various infiltrating immune cells, especially neutrophils. Moreover, some immune checkpoints had positive relationships with CSTF2 expression. CSTF2 silencing inhibited proliferation, invasion and migration, and promoted apoptosis in HepG2 cells. Western blotting analysis revealed that CSTF2 silencing inactivated the Wnt/β-catenin signaling pathway.ConclusionHigh CSTF2 expression not only correlates with unfavorable outcomes but also affects immune cell infiltration and immune checkpoint expression in HCC. CSTF2 silencing can alleviate the malignant phenotypes of hepatic cancer cell by inactivating the Wnt/β-catenin signaling pathway. These results indicate that CSTF2 can serve as a promising prognostic marker and therapeutic target for HCC patients.

A novel metabolic-immune related signature predicts prognosis and immunotherapy response in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is one of the most frequent types of lung cancer, with a high mortality and recurrence rate. This study aimed to design a RiskScore to predict the prognosis and immunotherapy response of LUAD patients due to a lack of metabolic and immune-related prognostic models. MethodsTo identify prognostic genes and generate a RiskScore, we conducted differential gene expression analysis, bulk survival analysis, Lasso regression analysis, and univariate and multivariate Cox regression analysis using TCGA-LUAD as a training subset. GSE31210 and GSE50081 were used as validation subsets to validate the constructed RiskScore. Following that, we explored the connection between RiskScore and clinicopathological characteristics, immune cells infiltration, and immunotherapy. In addition, we investigated into RiskScore's biological roles and constructed a Nomogram model. ResultsA RiskScore was identified consisting of five genes (DKK1, CCL20, NPAS2, GNPNAT1 and MELTF). In the RiskScore-high group, LUAD patients showed decreased overall survival rates and shorter progression-free survival. Multiple clinicopathological characteristics and immune cells infiltration in TME, in particular, have been linked to RiskScore. Of note, RiskScore-related genes have been implicated to substance metabolism, carcinogenesis, and immunological pathways, among other things. Finally, the C-index of the RiskScore-based Nomogram model was 0.804 (95% CI: 0.783–0.825), and time-dependent ROC predicted probabilities of 1-, 3- and 5-year survival for LUAD patients were 0.850, 0.848 and 0.825, respectively. ConclusionThe RiskScore, which integrated metabolic and immunological features with DKK1, CCL20, NPAS2, GNPNAT1, and MELTF, could reliably predict prognosis and immunotherapy response in LUAD patients. Moreover, the RiskScore-based Nomogram model had a promising clinical application.

Identification of a Necroptosis-Related Prognostic Index and Associated Regulatory Axis in Kidney Renal Clear Cell Carcinoma.

BackgroundKidney renal clear cell carcinoma (KIRC) is one of the most common aggressive malignancies in the genitourinary system with the high degree of immune infiltration. However, the role of necroptosis-related genes in the immune infiltration of KIRC and the impact on overall survival have not been adequately studied.MethodsDifferentially expressed necroptosis-related genes were identified based on The Cancer Genome Atlas (TCGA). Then, we constructed a necroptosis-related prognostic index (NRPI) through Lasso Cox regression analysis. The KIRC patients were divided into NRPI-high and NRPI-low groups by the median. Univariate and multivariate Cox regression analyses were used to determine NRPI as an independent prognostic factor. The role of NRPI was assessed through nomogram, GO/KEGG enrichment analyses, and immune cells infiltration. The efficacy of immunotherapy in KIRC patients was evaluated by TIDE. The immunohistochemistry was performed to verify the difference in protein expression between tumor samples and normal tissues from our hospital.ResultsWe found that NRPI-high patients had higher mortality. The multivariate Cox regression between the signature and multiple clinicopathological characteristics proved that NRPI could effectively and independently predict the prognosis of KIRC. The protein expression of three necroptosis-related genes constituting NRPI was significantly different between tumor and normal tissues. NRPI was closely related to immunologically relevant pathways and functions. The tumor microenvironment and immune infiltrating cells showed clear distinctions in NRPI-high and NRPI-low patients. The analysis of clinical treatments found that NRPI-low patients responded better to immunotherapy, while NRPI-high patients were more sensitive to targeted therapy. Furthermore, we identified a lncRNAs/miRNA/mRNA regulatory axis for KIRC.ConclusionIn general, NRPI was a promising biomarker in predicting the prognosis and responses to treatments in KIRC.