A novel machine learning model based on ubiquitin-related gene pairs and clinical features to predict prognosis and treatment effect in colon adenocarcinoma.

BACKGROUND: Ubiquitin and ubiquitin-like (UB/UBL) conjugations are essential post-translational modifications that contribute to cancer onset and advancement. In colon adenocarcinoma (COAD), nonetheless, the biological role, as well as the clinical value of ubiquitin-related genes (URGs), is unclear. The current study sought to design and verify a ubiquitin-related gene pairs (URGPs)-related prognostic signature for predicting COAD prognoses. METHODS: Using univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression, URGP's predictive signature was discovered. Signatures differentiated high-risk and low-risk patients. ROC and Kaplan-Meier assessed URGPs' signature. Gene set enrichment analysis (GSEA) examined biological nomogram enrichment. Chemotherapy and tumor immune microenvironment were also studied. RESULTS: The predictive signature used six URGPs. High-risk patients had a worse prognosis than low-risk patients, according to Kaplan-Meier. After adjusting for other clinical characteristics, the URGPs signature could reliably predict COAD patients. In the low-risk group, we found higher amounts of invading CD4 memory-activated T cells, follicular helper T cells, macrophages, and resting dendritic cells. Moreover, low-risk group had higher immune checkpoint-related gene expression and chemosensitivity. CONCLUSION: Our research developed a nomogram and a URGPs prognostic signature to predict COAD prognosis, which may aid in patient risk stratification and offer an effective evaluation method of individualized treatment in clinical settings.

Case report: an initially unresectable stage III pulmonary sarcomatoid carcinoma qith EGFR mutation achieving pathological complete response following neoadjuvant therapy with osimertinib plus chemotherapy.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) provide dramatic response to patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, the use of neoadjuvant therapy with EGFR-TKIs in EGFR-mutant NSCLC remains controversial, especially in pulmonary sarcomatoid carcinoma (PSC). One patient with initially unresectable stage III (cT4N0M0) PSC was found to carry EGFR mutation by the next generation sequencing. After neoadjuvant therapy with osimertinib plus chemotherapy, radical resection of the right upper lung lesion was achieved, and the pathological results reached pathological complete response (pCR). To the best of our knowledge, this is the first report of an EGFR-mutant patient with initially unresectable stage III PSC achieved pCR by neoadjuvant therapy with osimertinib plus chemotherapy. Therefore, neoadjuvant therapy with EGFR-TKIs may be a viable option for EGFR-mutant PSC patients.

DNA damage repair-related gene signature predicts prognosis and indicates immune cell infiltration landscape in skin cutaneous melanoma.

Background: DNA damage repair plays an important role in the onset and progression of cancers and its resistance to treatment therapy. This study aims to assess the prognostic potential of DNA damage repair markers in skin cutaneous melanoma (SKCM). Method: In this study, we have analyzed the gene expression profiles being downloaded from TCGA, GTEx, and GEO databases. We sequentially used univariate and LASSO Cox regression analyses to screen DNA repair genes associated with prognosis. Then, we have conducted a multivariate regression analysis to construct the prognostic profile of DNA repair-related genes (DRRGs). The risk coefficient is used to calculate the risk scores and divide the patients into two cohorts. Additionally, we validated our prognosis model on an external cohort as well as evaluated the link between immune response and the DRRGs prognostic profiles. The risk signature is compared to immune cell infiltration, chemotherapy, and immune checkpoint inhibitors (ICIs) treatment. Results: An analysis using LASSO-Cox stepwise regression established a prognostic signature consisting of twelve DRRGs with strong predictive ability. Disease-specific survival (DSS) is found to be lower among high-risk patients group as compared to low-risk patients. The signature may be employed as an independent prognostic predictor after controlling for clinicopathological factors, as demonstrated by validation on one external GSE65904 cohort. A strong correlation is also found between the risk score and the immune microenvironment, along with the infiltrating immune cells, and ICIs key molecules. The gene enrichment analysis results indicate a wide range of biological activities and pathways to be exhibited by high-risk groups. Furthermore, Cisplatin exhibited a considerable response sensitivity in low-risk groups as opposed to the high-risk incidents, while docetaxel exhibited a considerable response sensitivity in high-risk groups. Conclusions: Our findings provide a thorough investigation of DRRGs to develop an DSS-related prognostic indicator which may be useful in forecasting SKCM progression and enabling more enhanced clinical benefits from immunotherapy.

Development and Validation of Lactate Metabolism-Related lncRNA Signature as a Prognostic Model for Lung Adenocarcinoma.

Background: Lung cancer has been a prominent research focus in recent years due to its role in cancer-related fatalities globally, with lung adenocarcinoma (LUAD) being the most prevalent histological form. Nonetheless, no signature of lactate metabolism-related long non-coding RNAs (LMR-lncRNAs) has been developed for patients with LUAD. Accordingly, we aimed to develop a unique LMR-lncRNA signature to determine the prognosis of patients with LUAD. Method: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to derive the lncRNA expression patterns. Identification of LMR-lncRNAs was accomplished by analyzing the co-expression patterns between lncRNAs and LMR genes. Subsequently, the association between lncRNA levels and survival outcomes was determined to develop an effective signature. In the TCGA cohort, Cox regression was enlisted to build an innovative signature consisting of three LMR-lncRNAs, which was validated in the GEO validation cohort. GSEA and immune infiltration analysis were conducted to investigate the functional annotation of the signature and the function of each type of immune cell. Results: Fourteen differentially expressed LMR-lncRNAs were strongly correlated with the prognosis of patients with LUAD and collectively formed a new LMR-lncRNA signature. The patients could be categorized into two cohorts based on their LMR-lncRNA signatures: a low-risk and high-risk group. The overall survival of patients with LUAD in the high-risk group was considerably lower than those in the low-risk group. Using Cox regression, this signature was shown to have substantial potential as an independent prognostic factor, which was further confirmed in the GEO cohort. Moreover, the signature could anticipate survival across different groups based on stage, age, and gender, among other variables. This signature also correlated with immune cell infiltration (including B cells, neutrophils, CD4+ T cells, CD8+ T cells, etc.) as well as the immune checkpoint blockade target CTLA-4. Conclusion: We developed and verified a new LMR-lncRNA signature useful for anticipating the survival of patients with LUAD. This signature could give potentially critical insight for immunotherapy interventions in patients with LUAD.

LncRNA miR205HG hinders HNRNPA0 translation: anti-oncogenic effects in esophageal carcinoma.

Esophageal carcinoma (ESCA) affects 4 450 000 people and causes approximately 400 000 deaths annually worldwide, making it the sixth most lethal and eighth most common cancer. Patients with ESCA are often diagnosed at the later stages in which cancer cell metastasis is the main factor contributing to the low 5-year survival rate (< 20%) of this disease. Long noncoding RNAs (lncRNAs) are a group of regulatory RNAs with a length of > 200 nucleotides but which fail to encode proteins. In this study, by using real-time quantitative PCR, we found that the expression of the miR205 host gene (miR205HG; a lncRNA) was downregulated in ESCA tumors when compared with normal esophageal tissues or adjacent normal tissues of tumors. Furthermore, we demonstrated that miR205HG modulates the expression of extracellular matrix-related genes in ESCA cells. In the transwell assay, downregulation of miR205HG contributes to migration and invasion of ESCA cells. In relation to the mechanism, our data show that miR205HG interacts with heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0) mRNA and then hamper its translation by interacting with lin-28 homolog A (LIN28A). Altogether, we highlight that the miR205HG-HNRNPA0 axis is implicated in the migration and invasion of ESCA cells and that these members of this pathway may serve as therapeutic targets to inhibit metastasis of ESCA.

Oesophageal squamous cell carcinoma-associated IL-33 rewires macrophage polarization towards M2 via activating ornithine decarboxylase.

BACKGROUND: The tumour microenvironment primarily constitutes macrophages in the form of an immunosuppressive M2 phenotype, which promotes tumour growth. Thus, the development of methodologies to rewire M2-like tumour-associated macrophages (TAMs) into the M1 phenotype, which inhibits tumour growth, might be a critical advancement in cancer immunotherapy research. METHODS: The expressions of IL-33 and indicators related to macrophage polarization in oesophageal squamous cell carcinoma (ESCC) tissues and peripheral blood mononuclear cell (PBMC)-derived macrophages were determined. Inhibition of ornithine decarboxylase (ODC) with small interfering RNA was used to analyse the phenotype of macrophage polarization and polyamine secretory signals. CCK-8, wound-healing and Transwell assays were used to detect the proliferation and migration of ECA109 cells in vitro. The tumour xenograft assay in nude mice was used to examine the role of IL-33 in ESCC development in vivo. RESULTS: This study showed the substantially elevated IL-33 expression in ESCC tissues compared with the normal tissues. Additionally, enhanced infiltration of M2-like macrophages into the ESCC tumour tissue was also observed. We observed a strong correlation between the IL-33 levels and the infiltration of M2-like macrophages in ESCC tumours locally. Mechanistically, IL-33 induces M2-like macrophage polarization by activating ODC, a key enzyme that catalyses the synthesis of polyamines. Inhibition of ODC suppressed M2-like macrophage polarization. Finally, in vivo, we confirmed that IL-33 promotes tumour progression. CONCLUSIONS: This study revealed an oncogenic role of IL-33 by actively inducing M2-like macrophage differentiation; thus, contributing to the formation of an immunosuppressive ESCC tumour microenvironment. Thus, IL-33 could act as a novel target for cancer immunotherapies.

Circular RNA circNELL2 Acts as the Sponge of miR-127-5p to Promote Esophageal Squamous Cell Carcinoma Progression.

INTRODUCTION: Owing to its involvement in both the initiation and progression of various cancers, aberrant circular RNA (circRNA) expression has been researched extensively in the recent times. In the present study, we aim to investigate the effect of a novel circRNA has_circ_0025933 (circNELL2) in the progression of esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Sanger sequencing and the detection of circNELL2 level after RNase R or actinomycin D treatment were performed to identify the existence of cirNELL2 in ESCC cells. WST, EDU staining and colony-formation assay were used to assess the proliferation while transwell assay was used to evaluate the migration of ESCC cells. Luciferase assay, RNA pull down and the FISH assay were performed to verify the interaction between circNELL2 and miR-127-5p as well as miR-127-5p and CDC6. Xenograft model was carried out to evaluate the effect of circNELL2 in vivo. RESULTS: circNELL2 was proved to exist in ESCC cells. The up-regulated expression of circNELL2 in the clinical ESCC specimens was also verified. Next, function studies suggested that circNELL2 knockdown inhibited the proliferation of ESCC cells in vitro and in vivo, while circNELL2 overexpression promotes that of ESCC cells. Besides, this study mechanically predicted and verified the target miR of circNELL2, which is miR-127-5p. It was found that miR-127-5p was capable of reversing the effect of circNELL2 on ESCC cells. Moreover, miR-127-5p was also found to target CDC6 to participate in the regulation of cell phenotype. DISCUSSION: circNELL2 promoted the progression of ESCC cells via sponging miR-127-5p, and it has the potential to serve as a novel prognostic and therapeutic target for ESCC.

Clinicopathological features, survival outcomes, and appropriate surgical approaches for stage I acinar and papillary predominant lung adenocarcinoma.

BACKGROUND: Whether prognosis differs between lung acinar predominant adenocarcinoma (ACN) and papillary predominant adenocarcinoma (PAP) patients remains controversial. Furthermore, the appropriate surgical plan for each subtype is undetermined. METHODS: Data of stage I ACN or PAP patients from 2004 to 2015 were retrospectively reviewed by SEER*Stat 8.3.5. The primary outcome was overall survival (OS) and lung cancer specific survival (LCSS). RESULTS: 1531 patients (PAP, 484; ACN, 1047) were included. ACN patients had better OS (P = .001) and LCSS (P = .003) than PAP patients. Among stage I ACN patients, lobectomy with mediastinal lymph node dissection (Lob) (P = .001) or segmentectomy (Seg) (P = .003) provided a better OS than wedge resection (Wed). And ACN patients who received Lob had a equivalent LCSS, compared to those who received Seg (P = .895). For patients with PAP in stage I, those who received Lob tended to have a better prognosis than that received Seg (HR of OS, 0.605, 95% CI: 0.263-1.393; HR of LCSS, 0.541, 95% CI: 0.194-1.504) or Wed (HR of OS, 0.735, 95% CI: 0.481-1.123; HR of LCSS, 0.688, 95% CI: 0.402-1.180). CONCLUSIONS: Among patients with lung adenocarcinoma in stage I, those with ACN have a better OS and LCSS than that with PAP. For patients with stage I ACN, Seg and Lob, rather than Wed, seem to be an equivalent treatment choice; however, Seg is the prior option because it could preserve more lung function than Lob. For patients with PAP, Lob tends to be a better choice than Wed and Seg, although the prognostic difference between them is nonsignificant.

Beyond T Cells: Understanding the Role of PD-1/PD-L1 in Tumor-Associated Macrophages.

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 have attracted wide attention from researchers in the field of immunotherapy. PD-1/PD-L1 have been shown to exist in many types of cells in addition to T lymphocytes, and studies have accordingly extended from their suppressive effect on T cell activation and function to examining their role in other cells. In this review, we summarize recent research on PD-1/PD-L1 in macrophages, with the aim of furthering our understanding of PD-1/PD-L1 and their detailed roles in macrophages. This information may provide additional insights for researchers, enrich the basic theory of anti-PD-1/PD-L1 immunotherapy, and thus ultimately benefit more patients.

Case report: Crizotinib is effective in a patient with ROS1-rearranged pulmonary inflammatory myofibroblastic tumor.

OBJECTIVES: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor and is prevalent among children and adolescents. In recent years, following the emergence of high-throughput sequencing techniques, rearrangements in genes, such as ALK, ROS1, NTRK, RET, and PDGFRß, have been detected in a considerable proportion of IMT patients. However, the practice of targeted therapy for those patients remains extremely limited. In this study, we report about a 14-year-old boy diagnosed with pulmonary IMT with a mass measuring 12 × 8 cm in the right lower lobe. MATERIALS AND METHODS: Immunohistochemistry (IHC) assay and comprehensive next-generation sequencing (NGS) were performed on the biopsied tumor tissue. RESULTS: The IHC assay revealed an ALK-negative tumor, while NGS detected aTFG-ROS1 rearrangement. The patient achieved continuous remission after treatment with crizotinib (250 mg, bid). CONCLUSION: This case broadens the experience regarding targeted therapy forROS1-rearranged IMT and supports the use of broad molecular profiling testing for optimizing therapeutic options.