The role of tumor-associated macrophages in the radioresistance of esophageal cancer cells via regulation of the VEGF-mediated angiogenic pathway.

Tumor-associated macrophages (TAMs) are known to promote tumor growth, invasion, metastasis, and protumor angiogenesis, but the role of TAMs in evading radiotherapy in esophagus cancer remains unclear. In this study, we first induced TAMs from human monocytes (THP-1) and identified using immunofluorescence and Western blotting assays. We then co-cultured them with human esophageal cancer cell lines. CCK-8, colony formation, Transwell, scratch test, and TUNEL assays showed that TAMs could promote proliferation, survival rate, invasion, migration, and radioresistance and could inhibit apoptosis of the esophageal squamous carcinoma cell lines KYSE-150 and TE-1 before and after radiotherapy both in vivo and in vitro. Using LV-VEGFA-RNAi lentiviral vectors, we also found that TAMs could increase the expression of VEGFA and that inhibition of VEGFA could inhibit the biological function caused by TAMs. Finally, a Western blotting assay was used to evaluate the expression of various factors underlying the mechanism of TAMs. VEGFA, MAPK, P-MAPK, BCL-2, and Snail proteins were found to be overexpressed in co-cultured groups, whereas after VEGFA inhibition, MAPK, P-MAPK, BCL-2, and Snail proteins were found to be significantly downregulated in the radiotherapy group. These study results offer important information regarding the mechanism of radioresistance in esophageal cancer.

USP11 Exacerbates Radiation-Induced Pneumonitis by Activating Endothelial Cell Inflammatory Response via OTUD5-STING Signaling.

PURPOSE: Radiation-induced pneumonitis (RIP) seriously limits the application of radiation therapy in the treatment of thoracic tumors, and its etiology and pathogenesis remain elusive. This study aimed to elucidate the role of ubiquitin-specific peptidase 11 (USP11) in the progression of RIP and the associated underlying mechanisms. METHODS AND MATERIALS: Changes in cytokines and infiltrated immune cells were detected by enzyme-linked immunosorbent assays and immunohistochemistry after exposure to 20 Gy x-ray with whole-thorax irradiation. The effects of USP11 expression on endothelial cell proliferation and apoptosis were analyzed by costaining of CD31/Ki67 and CD31/caspase-3 in vivo, and the production of cytokines and reactive oxygen species was confirmed by reverse-transcription polymerase chain reaction and flow cytometry in vitro. Comprehensive proteome and ubiquitinome analyses were used for USP11 substrate screening after radiation. Results were verified by Western blotting and coimmunoprecipitation experiments. Recombinant adeno-associated virus lung vectors expressing OTUD5 were used for localized overexpression of OTUD5 in mouse pulmonary tissue, and immunohistochemistry was conducted to analyze cytokine expression. RESULTS: The progression of RIP was significantly alleviated by reduced expression of proinflammatory cytokines in both Usp11-knockout (Usp11-/-) mice and in mice treated with the USP11 inhibitor mitoxantrone. Likewise, the absence of USP11 resulted in decreased permeability of pulmonary vessels and neutrophils and macrophage infiltration. The proliferation rates of endothelial cells were prominently increased in the Usp11-/- lung, whereas apoptosis in Usp11-/- lungs decreased after irradiation compared with that observed in Usp11+/+ lungs. Conversely, USP11 overexpression increased proinflammatory cytokine expression and reactive oxygen species production in endothelial cells after radiation. Comprehensive proteome and ubiquitinome analyses indicated that USP11 overexpression upregulates the expression of several deubiquitinating enzymes, including USP22, USP33, and OTUD5. We demonstrate that USP11 deubiquitinates OTUD5 and implicates the OTUD5-STING signaling pathway in the progression of the inflammatory response in endothelial cells. CONCLUSIONS: USP11 exacerbates RIP by triggering an inflammatory response in endothelial cells both in vitro and in vivo, and the OTUD5-STING pathway is involved in the USP11-dependent promotion of RIP. This study provides experimental support for the development of precision intervention strategies targeting USP11 to mitigate RIP.

Contrastive learning-based histopathological features infer molecular subtypes and clinical outcomes of breast cancer from unannotated whole slide images.

The artificial intelligence-powered computational pathology has led to significant improvements in the speed and precision of tumor diagnosis, while also exhibiting substantial potential to infer genetic mutations and gene expression levels. However, current studies remain limited in predicting molecular subtypes and clinical outcomes in breast cancer. In this paper, we proposed a weakly supervised contrastive learning framework to address this challenge. Our framework first performed contrastive learning pretraining on a large number of unlabeled patches tiled from whole slide images (WSIs) to extract patch-level features. The gated attention mechanism was leveraged to aggregate patch-level features to produce slide feature that was then applied to various downstream tasks. To confirm the effectiveness of the proposed method, three public cohorts and one external independent cohort of breast cancer have been used to conducted evaluation experiments. The predictive powers of our model to infer gene expression, molecular subtypes, recurrence events and drug responses were validated across cohorts. In addition, the learned patch-level attention scores enabled us to generate heatmaps that were highly consistent with pathologist annotations and spatial transcriptomic data. These findings demonstrated that our model effectively established the high-order genotype-phenotype associations, thereby potentially extend the application of digital pathology in clinical practice.

Immune Checkpoint Inhibitors Serve as the First-Line Treatment for Advanced Head and Neck Cancer.

OBJECTIVES: Immune checkpoint inhibitor (ICI) therapy has demonstrated substantial benefits for certain patients. We try to evaluate the merits and demerits of each immunotherapy to aid clinical treatment. METHODS: We conducted a comprehensive search of the PubMed, Embase, and Cochrane databases for randomized clinical trials published as of June 10, 2023. Our study included published clinical trials of ICI monotherapy or combination therapy, along with data on treatment-related adverse events (TRAE). Data regarding survival efficacy and adverse events of each randomized controlled trial (RCT) were collected. The Bayesian random effects model was utilized for the network meta-analysis (NMA). RESULTS: This study incorporated 19 RCTs, involving 5900 patients. Among 14 treatment regimens, Pembrolizumab combined with chemotherapy emerged as the most promising primary treatment for overall survival (OS) and objective response rate (ORR). Toripalimab combined with chemotherapy exhibited the highest likelihood of becoming the primary treatment for extending progression-free survival (PFS). Durvalumab showed the lowest probability of adverse events, suggesting a safer profile compared with other drugs. Camrelizumab combined with chemotherapy demonstrated a heightened risk of adverse events. Dual ICI Nivolumab/Ipilimumab surpassed Durvalumab/Tremelimumab in terms of ORR and adverse events. The standard of care (SOC) regimen did not exhibit strong performance across the four outcome indicators. CONCLUSION: Our analysis suggests that the integration of chemotherapy agents with ICIs enhances its efficacy as a first-line treatment for patients with advanced head and neck cancer (HNC). LEVEL OF EVIDENCE: 1 Laryngoscope, 134:749-761, 2024.

Amelioration of Acute Radiation Dermatitis in Breast Cancer Patients by a Bioadhesive Barrier-Forming Gel (Episil): A Single-Center, Open, Parallel, Randomized, Phase I/II Controlled Trial.

Episil is a bioadhesive barrier-forming liquid gel that can relieve mucositis caused by radiotherapy (RT) and effectively relieve pain. The purpose of this trial is to compare the efficacy and safety of Episil in improving acute radiation dermatitis (ARD) in patients with breast cancer. This study included patients who met the criteria for postoperative RT for breast cancer. The primary end point was the grade of RD during treatment. A total of 102 patients were included in this study. The patients were grouped in a 2:1 ratio using the randomized number table method: 67 patients received Episil combined with conventional skin care (the Episil group), whereas the remaining 35 patients served as the control group and received conventional skin care only (the control group). According to the grading criteria of the Radiation Therapy Oncology Group (RTOG), the skin reaction rate and severity were significantly better in the Episil group than the control group (24.62%, 72.31%, 3.08, 0, 0 vs. 0, 85.71%, 14.29%, 0, 0, 0) across grades 0 to 4 (P < 0.05). The itchiness score exhibited s significant reduction in the Episil group as compared with the control group (P < 0.05). The results of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) showed that the overall health (z = -5.855, P < 0.001) and overall quality of life (z = -6.583, P < 0.001) were better in the Episil group than the control group after RT. Overall, in patients with breast cancer receiving RT, the topical application of Episil may significantly reduce the grading of ARD, alleviate patient symptoms, and improve the patient's overall quality of life.

Research progress and treatment of radiation enteritis and gut microbiota.

Radiation enteritis is a kind of intestinal radiation injury in patients with pelvic and retroperitoneal malignancies after radiotherapy, and its occurrence and development process are very complicated. At present, studies have confirmed that intestinal microecological imbalance is an important factor in the formation of this disease. Abdominal radiation causes changes in the composition of the flora and a decrease in its diversity, which is mainly manifested by a decrease in beneficial bacterial species such as Lactobacilli and Bifidobacteria. Intestinal dysbacteriosis aggravates radiation enteritis, weakens the function of the intestinal epithelial barrier, and promotes the expression of inflammatory factors, thereby aggravating the occurrence of enteritis. Given the role of the microbiome in radiation enteritis, we suggest that the gut microbiota may be a potential biomarker for the disease. Treatment methods such as probiotics, antibiotics, and fecal microbiota transplantation are ways to correct the microbiota and may be an effective way to prevent and treat radiation enteritis. Based on a review of the relevant literature, this paper reviews the mechanism and treatment of intestinal microbes in radiation enteritis.

Radiotherapy combined with immunotherapy could improve the immune infiltration of melanoma in mice and enhance the abscopal effect.

PURPOSE: To analyze the gene mutation, immune infiltration and tumor growth of primary tumor and distant tumor under different treatment modes. MATERIALS AND METHODS: Twenty B16 murine melanoma cells were injected subcutaneously into the of both sides of the thigh, simulating a primary tumor and a secondary tumor impacted by the abscopal effect, respectively. They were divided into blank control group, immunotherapy group, radiotherapy group, and radiotherapy combined immunotherapy group. During this period, tumor volume was measured, and RNA sequencing was performed on tumor samples after the test. R software was used to analyze differentially expressed genes, functional enrichment, and immune infiltration. RESULTS: We found that any treatment mode could cause changes in differentially expressed genes, especially the combination treatment. The different therapeutic effects might be caused by gene expression. In addition, the proportions of infiltrating immune cells in the irradiated and abscopal tumors were different. In the combination treatment group, T-cell infiltration in the irradiated site was the most obvious. In the immunotherapy group, CD8+ T-cell infiltration in the abscopal tumor site was obvious, but immunotherapy alone might have a poor prognosis. Whether the irradiated or abscopal tumor was evaluated, radiotherapy combined with anti-programmed cell death protein 1 (anti-PD-1) therapy produced the most obvious tumor control and might have a positive impact on prognosis. CONCLUSION: Combination therapy not only improves the immune microenvironment but may also have a positive impact on prognosis.

Identification of TUBB4A as a Prognostic Biomarker of Melanoma by Transcriptomic Data and In Vitro Experiments.

Background: Melanoma is one of the most malignant skin carcinomas with high metastatic potential. Increasing evidence has demonstrated that ß-tubulin 4A (TUBB4A) plays a key role in the development and progression of several types of human cancer. However, the potential function of TUBB4A in cutaneous melanoma remains to be determined. Methods: We first performed a differential expression analysis based on skin melanoma tissues and normal tissues from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets and then a survival analysis to identify prognostic-related key genes. We further conducted in vitro biochemical experiments to verify the functional roles of the key gene TUBB4A. Two small-molecule inhibitors of TUBB4A, Dihydroartemisinin (DHA) and Nocodazole, were used to validate the effect of TUBB4A on the apoptosis and cell cycle of melanoma cells. Results: We found that TUBB4A expression was positively correlated to the overall survival (OS) of cutaneous melanoma patients. The coexpressed genes with TUBB4A were enriched in melanoma-related pathways and functions. The experimental results showed that knockdown of TUBB4A inhibited the proliferation and migration of A375 and B16-F10 melanoma cells. Moreover, DHA and Nocodazole promoted the apoptosis of melanoma cells and blocked the melanoma tumor cell cycle in the G2/M stage. Conclusion: TUBB4A may be a prognostic biomarker and therapeutic target for melanoma.

The relevance of ototoxicity induced by radiotherapy.

BACKGROUND: The risk of ototoxicity, characterized by hearing impairment, tinnitus, or middle ear inflammation, is elevated in both child and adult cancer survivors who have undergone head-neck or brain radiation, or a combination of the two. To provide optimal care for these cancer survivors and minimize subsequent complications, it is crucial to comprehend the relationship between radiotherapy and ototoxicity. METHODS: A comprehensive search of databases, including the Cochrane Library, PubMed, Embase, and Web of Science, was conducted from the inception of the knowledge base up until January 2023. The metafor-package was employed to compare ototoxicity rates in individuals receiving radiotherapy. Two independent assessors extracted data and analyzed targets using a random-effects model. RESULTS: Out of the 28 randomized controlled trials (RCTs) included in the analysis, 25 were prospective RCTs. Subgroup analysis revealed that mean cochlear radiation dose, primary tumor location, radiotherapy modality, and patient age significantly influenced total hearing impairment. Intensity-modulated radiotherapy was associated with less ototoxicity than 2D conventional radiotherapy (OR, 0.53; 95% CI, 0.47-0.60; P = 0.73; I2 = 0%). Stereotactic radiotherapy appeared to be a superior option for hearing preservation compared to radiosurgery (OR, 1.44; 95% CI, 1.00-2.07; P = 0.69; I2 = 0%). Children demonstrated a higher risk of hearing impairment than adults. More than 50% of patients with vestibular neuroadenoma experienced hearing impairment following radiation therapy. A strong association was observed between the average cochlear radiation dose and hearing impairment. Increased cochlear radiation doses may result in a heightened risk of hearing impairment. CONCLUSION: Several risk factors for radiation-induced hearing impairment were identified in this study. High cochlear radiation doses were found to exacerbate the risk of hearing impairment resulting from radiation therapy.

The Regulation of Exosome-Mediated miR-132-3p/miR-132-3p-UUU on Radiation-Induced Esophageal Injury.

Radiation-induced esophageal injury (RIEI) is a major dose-limiting complication of radiotherapy, mainly acute esophagitis. However, understanding of radiation injury and repair mechanisms in esophageal epithelial cells remains limited. MiR-132-3p and its uridylated isoform (miR-132-3p-UUU) are upregulated in radiation esophageal injury, yet their role in radiation-induced esophageal injury progression remains unexplored. We expressed miR-132-3p and its uridine form in irradiated human esophageal epithelial cells (HEEC) and secreted exosomes was examined by real-time polymerase chain reaction (RT-PCR). Cell proliferation, migration, apoptosis and colony formation were used to determine biological effects. Cell cycle assays and dual luciferase reporter assays were used to assess the relationship between miR-132-3p and its uridylated isoforms and MEF2A. The addition of miR-132-3p mimics or overexpression of miR-132-3p significantly inhibited the proliferation and migration of esophageal epithelial cells (HEEC cells as well as primary cells) and increased radiation damage. This was reversed by its uridylated isoform by reducing binding to MEF2A and regulating the cell cycle. Furthermore, miR-132-3p and its triuridylated isomer also regulate apoptosis after irradiation through pathways other than reactive oxygen species (ROS). In conclusion, our data reveal that radiation-induced miR-132-3p uridylation and exosome-mediated intercellular communication and tri-uridylated isoforms are protective against radiation-induced esophageal injury. Furthermore, miR-132-3p offers new opportunities as a promising biomarker widely present in human body fluids for the prediction of radiation esophagitis as a biomarker.

Endoplasmic Reticulum Stress Could Predict the Prognosis of Cervical Cancer and Regulate the Occurrence of Radiation Mucositis.

The endoplasmic reticulum (ER) is an important cellular organelle, and ER dysfunction has an important impact on a variety of biological processes. In this study, we explored the role of ER stress in cervical cancer by establishing a prognostic model related to ER stress. This study included 309 samples from the TCGA database and 15 pairs of RNA sequencing data before and after radiotherapy. ER stress characteristics were obtained by the LASSO regression model. The prognostic value of risk characteristics was analyzed by Cox regression, Kaplan‒Meier, and ROC curves. The effects of radiation and radiation mucositis on ER stress were evaluated. We found that ER stress-related genes were differentially expressed in cervical cancer and could predict its prognosis. The LASSO regression model suggested that risk genes had a strong ability to predict prognosis. In addition, the regression suggests that the low-risk group may benefit from immunotherapy. Cox regression analysis showed that FOXRED2 and N staging could be independent factors affecting prognosis. ERN1 was significantly affected by radiation and may be related to the occurrence of radiation mucositis. In conclusion, ER stress activation might have a high value in the treatment and prognosis of cervical cancer and has good clinical prospects.

LncRNA DGCR5 Silencing Enhances the Radio-Sensitivity of Human Esophageal Squamous Cell Carcinoma via Negatively Regulating the Warburg Effect.

Recently, long noncoding RNAs (lncRNAs) and the Warburg effect have been reported to play important roles in the radio-sensitivity of tumor cells. Survival correlates with pathologic responses to chemoradiotherapy and improving responses to radiation may translate into improved survival. This study aims to examine the effects and mechanisms of lncRNA DGCR5 and the Warburg effect on ESCC cell radiosensitivity. Levels of DGCR5, miR-195 and hexokinase 2 (HK2) expression in ESCC tissues and cells were determined and their clinical significance was analyzed. TE-1 and KYSE150 cells received a 6 Gy dose of X-ray radiation and their survival, proliferation and apoptosis were evaluated using colony formation assays, CCK-8 assays, and flow cytometry, respectively. Lactic acid production and glucose consumption were also examined in both cell types. Finally, the expression of apoptotic proteins was assessed using Western blotting. Analysis revealed that DGCR5 and HK2 were overexpressed in ESCC, while miR-195 was under expressed. Moreover, it was demonstrated that down-regulation of DGCR5 inhibited cell proliferation and promoted apoptosis, resulting in increased radiosensitivity by inhibition of the Warburg Effect. Conversely, overexpression of DGCR5 exhibited an opposite phenomenon in vitro. When investigating the mechanism, we identified that miR-195 was predicted to be a direct downstream target of DGCR5. Meanwhile, HK2 was predicted to be a direct downstream target of miR-195. Dual-luciferase reporter assays verified the direct interaction between these molecules. Finally, in vivo experiments were utilized to validate that knockdown of DGCR5 suppressed the Warburg effect via targeting of the miR-195/HK2 axis to increase the radiosensitivity of ESCC. Our study reveals that down-regulation of DGCR5 resulted in inhibition of the Warburg effect through interaction with the miR-195/HK2 axis increasing ESCC cell apoptosis after irradiation, thus enhancing cell radiosensitivity.

Immune infiltration could predict the efficacy of short-term radiotherapy in patients with cervical cancer.

Radiotherapy is the main treatment for cervical cancer. It is usually applied alone or in combination with surgery and/or chemotherapy. To explore the association between immune microenvironment of cervical cancer and radiotherapy response, we collected 20 paired cervical cancer tumor samples before and after radiotherapy and partial clinical information. With paired-end RNA-seq, we quantified the immune infiltration and tumor purity of these samples, and obtained 6350 differentially expressed genes before and after radiotherapy. With the help of R language, the function enrichment analysis and 22 immune cells infiltration analysis were carried out. Moreover, we built a random forest model based on the immune microenvironment to predict the short-term efficacy of radiotherapy. We found that the effect of radiotherapy on the immune microenvironment of stage III and IV cervical cancer patients was weaker than that of stage I and II cervical cancer patients. Radiotherapy can significantly reduce the tumor purity and increase immune infiltration. The proportions of the immune infiltrating cells are predictive of the radiotherapy efficacy. In addition, the local mucositis caused by radiotherapy can improve the curative effect of radiotherapy.

Optimal treatment strategy and prognostic analysis for patients with non-metastatic pT4 colon adenocarcinoma.

Objective: This study endeavored to explore the optimal treatment strategy and conduct a prognostic analysis for patients diagnosed with pT4M0 (pathologic stage T4) colon adenocarcinoma (COAD). Methods and materials: A total of 8,843 patients diagnosed with pT4M0 COAD between January 2010 and December 2015 were included in this study from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were randomly divided into a training set and an internal validation set using a 7:3 ratio. Variables that demonstrated statistical significance (P<0.05) in univariate COX regression analysis or held clinical significance were incorporated into the multivariate COX regression model. Subsequently, this model was utilized to formulate a nomogram. The predictive accuracy and discriminability of the nomogram were assessed using the C-index, area under the curve (AUC), and calibration curves. Decision curve analysis (DCA) was conducted to confirm the clinical validity of the model. Results: In the entire SEER cohort, the 3-year overall survival (OS) rate (74.22% vs. 63.20%, P<0.001) and the 3-year cancer-specific survival (CSS) rate (76.25% vs. 66.98%, P<0.001) in the surgery combined with postoperative adjuvant therapy (S+ADT) group surpassed those in the surgery (S) group. Multivariate COX regression analysis of the training set unveiled correlations between age, race, N stage, serum CEA (carcinoembryonic antigen), differentiation, number of resected lymph nodes, and treatment modalities with OS and CSS. Nomograms for OS and CSS were meticulously crafted based on these variables, achieving C-indexes of 0.692 and 0.690 in the training set, respectively. The robust predictive ability of the nomogram was further affirmed through receiver operating characteristic (ROC) and calibration curves in both the training and validation sets. Conclusion: In individuals diagnosed with pT4M0 COAD, the integration of surgery with adjuvant chemoradiotherapy demonstrated a substantial extension of long-term survival. The nomogram, which incorporated key factors such as age, race, differentiation, N stage, serum CEA level, tumor size, and the number of resected lymph nodes, stood as a dependable tool for predicting OS and CSS rates. This predictive model held promise in aiding clinicians by identifying high-risk patients and facilitating the development of personalized treatment plans.

Differentially Expressed mRNAs and Potential Mechanisms of Radiation-Induced TUT4-/- Esophageal Cell Injury.

Radiation-induced esophageal injury remains a limitation for the process of radiotherapy for lung and esophageal cancer patients. Esophageal epithelial cells are extremely sensitive to irradiation, nevertheless, factors involved in the radiosensitivity of esophageal epithelial cells are still unknown. Terminal uridyl transferase 4 (TUT4) could modify the sequence of miRNAs, which affect their regulation on miRNA targets and function. In this study, we used transcriptome sequencing technology to identify mRNAs that were differentially expressed before and after radiotherapy in esophageal epithelial cells. We further explored the mRNA expression profiles between wild-type and TUT4 knockout esophageal epithelial cells. Volcano and heatmap plots unsupervised hierarchical clustering analysis were performed to classify the samples. Enrichment analysis on Gene Ontology functional annotations and Kyoto Encyclopedia of Genes and Genomes pathways was performed. We annotated differential genes from metabolism, genetic information processing, environmental information processing, cellular processes, and organismal systems human diseases. The aberrantly expressed genes are significantly enriched in irradiation-related biological processes, such as DNA replication, ferroptosis, and cell cycle. Moreover, we explored the distribution of transcription factor family and its target genes in differential genes. These mRNAs might serve as therapeutic targets in TUT4-related radiation-induced esophageal injury.

Interferon regulatory factor 1-triggered free ubiquitin protects the intestines against radiation-induced injury via CXCR4/FGF2 signaling.

Radiation-induced intestinal injury is a serious concern during abdominal and pelvic cancers radiotherapy. Ubiquitin (Ub) is a highly conserved protein found in all eukaryotic cells. This study aims to explore the role and mechanism of free Ub against radiogenic intestinal injury. We found that free Ub levels of irradiated animals and human patients receiving radiotherapy were upregulated. Radiation-induced Ub expression was associated with the activation of interferon regulatory factor 1 (IRF1). Intraperitoneal injection of free Ub significantly reduced the mortality of mice following 5-9 Gy total body irradiation (TBI) through the Akt pathway. Free Ub facilitates small intestinal regeneration induced by TBI or abdominal irradiation. At the cellular level, free Ub or its mutants significantly alleviated cell death and enhanced the survival of irradiated intestinal epithelial cells. The radioprotective role of free Ub depends on its receptor CXCR4. Mechanistically, free Ub increased fibroblast growth factor-2 (FGF2) secretion and consequently activated FGFR1 signaling following radiation in vivo and in vivo. Thus, free Ub confers protection against radiation-induced intestinal injury through CXCR4/Akt/FGF2 axis, which provides a novel therapeutic option.

Establish immune-related gene prognostic index for esophageal cancer.

Background: Esophageal cancer is a tumor type with high invasiveness and low prognosis. As immunotherapy has been shown to improve the prognosis of esophageal cancer patients, we were interested in the establishment of an immune-associated gene prognostic index to effectively predict the prognosis of patients. Methods: To establish the immune-related gene prognostic index of esophageal cancer (EC), we screened 363 upregulated and 83 downregulated immune-related genes that were differentially expressed in EC compared to normal tissues. By multivariate Cox regression and weighted gene coexpression network analysis (WGCNA), we built a prognostic model based on eight immune-related genes (IRGs). We confirmed the prognostic model in both TCGA and GEO cohorts and found that the low-risk group had better overall survival than the high-risk group. Results: In this study, we identified 363 upregulated IRGs and 83 downregulated IRGs. Next, we found a prognostic model that was constructed with eight IRGs (OSM, CEACAM8, HSPA6, HSP90AB1, PCSK2, PLXNA1, TRIB2, and HMGB3) by multivariate Cox regression analysis and WGCNA. According to the Kaplan-Meier survival analysis results, the model we constructed can predict the prognosis of patients with esophageal cancer. This result can be verified by the Gene Expression Omnibus (GEO). Patients were divided into two groups with different outcomes. IRGPI-low patients had better overall survival than IRGPI-high patients. Conclusion: Our findings indicated the potential value of the IRGPI risk model for predicting the prognosis of EC patients.

M6A regulator expression patterns predict the immune microenvironment and prognosis of non-small cell lung cancer.

BACKGROUND: The m6A methylation modification is one of the most common mRNA modifications, and involved in a variety of biological processes, such as cell death, cancer stem cell formation and tumorigenesis. Increasing evidences have demonstrated that the expression patterns of m6A regulators are significantly correlated with PD-L1 level some solid tumors, but few study has explored the function of m6A regulators in the immune microenvironment and prognosis in non-small cell lung cancer (NSCLC). METHODS: Survival analysis was independently conducted for 20 m6A regulators to explore their prognostic value in NSCLC, and then the prognostic risk model based on m6A regulator expression profiles is built to stratify NSCLC patients. Also, the correlation analysis between immune infiltrating cells and m6A regulators is used to reveal the impact of m6A on immune microenvironment of NSCLC. Furthermore, to explore the function of m6A as biomarker of anit-PD-L1 therapeutic effect, we explored the associations of tumor mutation burden (TMB) and PD-L1 levels to 20 m6A regulator expression patterns in NSCLC. RESULTS: First, the expressions of 20 m6A regulators in NSCLC tissues were significantly increased compared to normal tissues. Survival analysis revealed that three genes, METTL3, HNRNPC and VIRMA, were markedly correlated to the prognosis of NSCLC patients. In particular, cox regression analysis verified that METTL3 could be used as an independent prognostic factor to predict the survival rate of NSCLC patients. Second, the risk prognostic model built on seven m6A regulators can effectively stratify NSCLC patients, and the low-risk subgroup had better prognosis compared to high-risk group. Finally, a few m6A regulators showed significant associations with immune microenvironment, as well as TMB and PD-L1 level, suggesting that the m6A RNA methylation is indicative of therapeutic effect of anti-PD-L1 treatment. CONCLUSION: Our study identified some m6A regulatory factors as independent risk factors for the prognosis of NSCLC, and the expression patterns of m6A regulators are also correlated to the immune infiltration, as well as TMB and PD-L1 level in NSCLC. The m6A regulators could be used as biomarkers indicative of immunotherapy to NSCLC patients.

KIF26B in the Prognosis and Immune Biomarking of Various Cancers: A Pan-Cancer Study.

KIF26B has been identified as an oncogene in several tumors; however, its utility as a prognostic indicator for various cancers has not yet been comprehensively evaluated. Here, we first examined how KIF26B intervenes in thirty-three cancers within the TCGA database, including potential immunological functions, and how it affects the prognosis. Based on the open databases TCGA, TIMER2, GEPIA2, GTEx, CPTAC, and HPA, we found that, when compared with normal tissues, KIF26B is overexpressed in 22 tumor tissues. Following a survival analysis, a relationship between the expression of KIF26B and the prognosis of various cancers was observed. Among the genetic alterations assessed, mutations were the most frequent. On the contrary, high phosphorylation levels of S977 were detected in breast cancer, KIRC, LUAD, and UCEC. We also found positive or negative correlations between KIF26B and the immune infiltration of endothelial cells and cancer-associated fibroblast infiltration. This could imply that patients may benefit from immunotherapy. Finally, KEGG pathways and GO enrichment analyses were implemented to identify the molecular mechanisms of KIF26B. This study illustrates the function of KIF26B from a pan-cancer perspective and offers a new horizon for cancer prognostic and immunotherapeutic investigations.

B4GALT5 high expression associated with poor prognosis of hepatocellular carcinoma.

BACKGROUND: B4GALT5 is postulated to be an important protein in sugar metabolism that catalyzes the synthesis of lactosylceramide (LacCer). However, its role in hepatocellular carcinoma (HCC) remains unknown. METHOD: We characterized the expression of B4GALT5 in HCC tissue compared to normal tissue, and explored its function of B4GALT5 in HCC by enrichment analysis based on its co-expressed gene set. Next, we checked whether B4GALT5 expression is correlated to immune infiltration level and clinical prognosis in hepatocellular carcinoma. Finally, we verified the expression of B4GALT5 using clinical samples evaluated by RT-PCR, and conducted in vitro experiments with B4GALT5-knockdown HCC cells to investigate the function of B4GALT5 in the HCC cell proliferation, migration and invasion. RESULTS: We found B4GALT5 mRNA and protein expression levels were significantly high in HCC tissue compared to normal tissue. The enrichment analysis of the gene sets that co-expressed with B4GALT5 showed specificity in HCC-related pathways and functions. Also, the expression pattern of B4GALT5 was significantly related to the immune infiltration level, especially CD4+ T cell and macrophage cells. B4GALT5 higher mRNA expression was associated with poor overall survival (OS) in HCC patients. Furthermore, In vitro experiments showed that depletion of B4GALT5 significantly inhibited HCC cell proliferation, migration and invasion. This study revealed the function and its mediated pathways of B4GALT5 in HCC, indicating that B4GALT5 may serve as a prognostic biomarker of HCC.