Deciphering the molecular and clinical characteristics of TREM2, HCST, and TYROBP in cancer immunity: A comprehensive pan-cancer study.

Background: Hematopoietic cell signal transducer (HCST) and tyrosine kinase-binding protein (TYROBP) are triggering receptors expressed on myeloid cells 2 (TREM2), which are pivotal in the immune response to disease. Despite growing evidence underscoring the significance of TREM2, HCST, and TYROBP in certain forms of tumorigenesis, a comprehensive pan-cancer analysis of these proteins is lacking. Methods: Multiple databases were synthesized to investigate the relationship between TREM2, HCST, TYROBP, and various cancer types. These include prognosis, methylation, regulation by long non-coding RNAs and transcription factors, immune signatures, pathway activity, microsatellite instability (MSI), tumor mutational burden (TMB), single-cell transcriptome profiling, and drug sensitivity. Results: TREM2, HCST, and TYROBP displayed extensive somatic changes across numerous tumors, and their mRNA expression and methylation levels influenced patient outcomes across multiple cancer types. long non-coding RNA (lncRNA) -messenger RNA (mRNA) and TF-mRNA regulatory networks involving TREM2, HCST, and TYROBP were identified, with lncRNA MEG3 and the transcription factor SIP1 emerging as potential key regulators. Further immune analyses indicated that TREM2, HCST, and TYROBP play critical roles in immune-related pathways and macrophage differentiation, and may be significantly associated with TGF-ß and SMAD9. Furthermore, the expression of TREM2, HCST, and TYROBP correlated with the immunotherapy markers TMB and MSI, and influenced sensitivity to immune-targeted drugs, thereby indicating their potential as predictors of immunotherapy outcomes. Conclusion: This study offers valuable insights into the roles of TREM2, HCST, and TYROBP in tumor immunotherapy, suggesting their potential as prognostic markers and therapeutic targets for various cancers.

Exploring the relationship between metabolism and immune microenvironment in osteosarcoma based on metabolic pathways.

BACKGROUND: Metabolic remodeling and changes in tumor immune microenvironment (TIME) in osteosarcoma are important factors affecting prognosis and treatment. However, the relationship between metabolism and TIME needs to be further explored. METHODS: RNA-Seq data and clinical information of 84 patients with osteosarcoma from the TARGET database and an independent cohort from the GEO database were included in this study. The activity of seven metabolic super-pathways and immune infiltration levels were inferred in osteosarcoma patients. Metabolism-related genes (MRGs) were identified and different metabolic clusters and MRG-related gene clusters were identified using unsupervised clustering. Then the TIME differences between the different clusters were compared. In addition, an MRGs-based risk model was constructed and the role of a key risk gene, ST3GAL4, in osteosarcoma cells was explored using molecular biological experiments. RESULTS: This study revealed four key metabolic pathways in osteosarcoma, with vitamin and cofactor metabolism being the most relevant to prognosis and to TIME. Two metabolic pathway-related clusters (C1 and C2) were identified, with some differences in immune activating cell infiltration between the two clusters, and C2 was more likely to respond to two chemotherapeutic agents than C1. Three MRG-related gene clusters (GC1-3) were also identified, with significant differences in prognosis among the three clusters. GC2 and GC3 had higher immune cell infiltration than GC1. GC3 is most likely to respond to immune checkpoint blockade and to three commonly used clinical drugs. A metabolism-related risk model was developed and validated. The risk model has strong prognostic predictive power and the low-risk group has a higher level of immune infiltration than the high-risk group. Knockdown of ST3GAL4 significantly inhibited proliferation, migration, invasion and glycolysis of osteosarcoma cells and inhibited the M2 polarization of macrophages. CONCLUSION: The metabolism of vitamins and cofactors is an important prognostic regulator of TIME in osteosarcoma, MRG-related gene clusters can well reflect changes in osteosarcoma TIME and predict chemotherapy and immunotherapy response. The metabolism-related risk model may serve as a useful prognostic predictor. ST3GAL4 plays a critical role in the progression, glycolysis, and TIME of osteosarcoma cells.

Identification of molecular subtypes and a risk model based on inflammation-related genes in patients with low grade glioma.

Lower grade gliomas (LGGs) exhibit invasiveness and heterogeneity as distinguishing features. The outcome of patients with LGG differs greatly. Recently, more and more studies have suggested that infiltrating inflammation cells and inflammation-related genes (IRGs) play an essential role in tumorigenesis, prognosis, and treatment responses. Nevertheless, the role of IRGs in LGG remains unclear. In The Cancer Genome Atlas (TCGA) cohort, we conducted a thorough examination of the predictive significance of IRGs and identified 245 IRGs that correlated with the clinical prognosis of individuals diagnosed with LGG. Based on unsupervised cluster analysis, we identified two inflammation-associated molecular clusters, which presented different tumor immune microenvironments, tumorigenesis scores, and tumor stemness indices. Furthermore, a prognostic risk model including ten prognostic IRGs (ADRB2, CD274, CXCL12, IL12B, NFE2L2, PRF1, SFTPC, TBX21, TNFRSF11B, and TTR) was constructed. The survival analysis indicated that the IRGs risk model independently predicted the prognosis of patients with LGG, which was validated in an independent LGG cohort. Moreover, the risk model significantly correlated with the infiltrative level of immune cells, tumor mutation burden, expression of HLA and immune checkpoint genes, tumorigenesis scores, and tumor stemness indices in LGG. Additionally, we found that our risk model could predict the chemotherapy response of some drugs in patients with LGG. This study may enhance the advancement of personalized therapy and improve outcomes of LGG.

A tumor microenvironment-based prognostic index for osteosarcoma.

BACKGROUND: The tumor microenvironment (TME) has a central role in the oncogenesis of osteosarcomas. The composition of the TME is essential for the interaction between tumor and immune cells. The aim of this study was to establish a prognostic index (TMEindex) for osteosarcoma based on the TME, from which estimates about patient survival and individual response to immune checkpoint inhibitor (ICI) therapy can be deduced. METHODS: Based on osteosarcoma samples from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, the ESTIMATE algorithm was used to estimate ImmuneScore and StromalScore. Combined differentially expressed gene analysis, weighted gene co-expression network analyses, the Least Absolute Shrinkage and Selection Operator regression and stepwise regression to construct the TMEindex. The prognostic role of TMEindex was validated in three independent datasets. The molecular and immune characteristics of TMEindex and the impact on immunotherapy were then comprehensively investigated. The expression of TMEindex genes in different cell types and its effects on osteosarcoma cells were explored by scRNA-Seq analysis and molecular biology experiments. RESULTS: Fundamental is the expression of MYC, P4HA1, RAMP1 and TAC4. Patients with high TMEindex had worse overall survival, recurrence-free survival, and metastasis-free survival. TMEindex is an independent prognostic factor in osteosarcoma. TMEindex genes were mainly expressed in malignant cells. The knockdown of MYC and P4HA1 significantly inhibited the proliferation, invasion and migration of osteosarcoma cells. A high TME index is related to the MYC, mTOR, and DNA replication-related pathways. In contrast, a low TME index is related to immune-related signaling pathways such as the inflammatory response. The TMEindex was negatively correlated with ImmuneScore, StromalScore, immune cell infiltration, and various immune-related signature scores. Patients with a higher TMEindex had an immune-cold TME and higher invasiveness. Patients with a low TME index were more likely to respond to ICI therapy and achieve clinical benefit. In addition, the TME index correlated with response to 29 oncologic drugs. CONCLUSIONS: The TMEindex is a promising biomarker to predict the prognosis of patients with osteosarcoma and their response to ICI therapy, and to distinguish the molecular and immune characteristics.

A human pan-cancer system analysis of regulator of chromatin condensation 2.

Regulation of chromosome condensation 2 (RCC2) is associated with the cell cycle and is a crucial regulator of the chromatin condensation 1 (RCC1) family. The members of this family were normally regulators in the process of DNA replication and nucleocytoplasmic transport. RCC2 overexpression may lead to tumor formation and poor prognosis in some tumors including breast cancer and lung adenocarcinoma. However, the possible role of RCC2 in tumor formation and its prognostic function remains unclear. In this study, expression analysis from databases including The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were combined to perform the first integrative and comprehensive analysis of RCC2 in human pan-cancer. RCC2 was highly expressed in most tumors which may lead to a poor prognosis. RCC2 expression was associated with immune/stromal infiltration, immune checkpoints, tumor mutational burden, and microsatellite instability. Thus, RCC2 could be a novel biomarker for prognosis and a promising cancer therapy target.

Preservation of the integrity of facial nerve in vestibular schwannoma microsurgery: A consecutive study of 127 clinical cases focusing on nervus intermedius.

Background: Nervus intermedius (NI) injuries are not given enough attention by neurosurgeons during vestibular schwannoma (VS) surgery. Preservation of NI function is essential for the integrity and continuity of the facial nerve, although this can be challenging. We identified the risk factors for NI injury and proposed our experience for optimizing NI preservation based on our cases. Methods: We retrospectively analyzed clinical data from a consecutive series of 127 patients with VS who underwent microsurgery via the retrosigmoid approach from 2017 to 2021 at our institution. The baseline characteristics of the patients were collected from the medical records, and the incidence of NI dysfunction symptoms was obtained by outpatient and online video follow-up 6 months after surgery. The surgical procedures and techniques used were described in detail. The data were analyzed in relation to sex, age, tumor location (left or right), Koos grading scale, internal acoustic canal (IAC) invasion (TFIAC Classification), brainstem adhesion, tumor characteristics (cystic or solid), tumor necrosis, and preoperative House-Brackmann (HB) grading by univariate and multivariate analyses. Results: Gross tumor removal was achieved in 126 (99.21%) patients. Subtotal removal was performed on one patient (0.79%). Twenty-three of our cases exhibited facial nerve palsy preoperatively; 21 patients had HB grade II facial palsy, and two had HB grade III. Two months after surgery, 97 (76.38%) patients had normal function of the motor portion of the facial nerve; 25 (19.69%) patients had HB Grade II facial palsy, five had Grade III (3.94%), and zero (0%) had Grade IV. Postoperatively, 15 patients experienced newly gained dry eyes (11.81%), whereas 21 cases of lacrimal disturbances (16.54%), nine of taste disturbances (7.09%), seven of xerostomia (5.51%), five of nasal hypersecretions (3.94%), and seven of hypersalivation (5.51%) were identified in our cases. Univariate and multivariate analyses revealed that the Koos grading scale and tumor characteristics (solid or cystic) were correlated with NI injury (p <0.01). Conclusion: The data in this study demonstrate that although the motor function of the facial nerve is well preserved, NI disturbance is still common after VS surgery. Maintaining the integrity and continuity of the facial nerve is key to NI function. Performing bidirectional and subperineurium dissection based on even and adequate debulking is beneficial for NI preservation in VS surgery. Higher Koos grading and cystic characteristics of VS are associated with postoperative NI injuries. These two parameters can be used to guide the delineation of surgical strategy and predict the prognosis of NI function preservation.

PLODs: Novel prognostic biomarkers and potential immunotherapy targets for head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) comprise a group of malignant tumors arising from the squamous epithelium of the oral cavity, pharynx, and larynx. HNSCC is the 6th most common cancer in the world, with approximately 650,000 new cases and 400,000 deaths annually. Although survival rates have improved, HNSCC therapy may result in short - or long-term morbidity in approximately 50% of cases. Previous studies have also indicated that the overexpression of procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenases (PLOD) family proteins could lead to certain diseases or even tumors. However, there has been no dedicated evaluation of the relationship between PLOD family members and HNSCC. Here we used data from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA) databases to explore the potential role of PLOD family proteins in HNSCC. Our evaluations suggest that increased expression of PLOD family proteins may be associated with poorer prognosis and increased immune infiltration in HNSCC, making these proteins a potential biomarker for personalized treatment of HNSCC.

Pan-cancer analyses reveal molecular and clinical characteristics of cuproptosis regulators.

Imbalance in copper homeostasis can be lethal. A recent study found that excess copper induces cell death in a way that has never been characterized before, which is dependent on mitochondrial stress and is referred to as "cuproptosis." The role of cuproptosis in tumors has not yet been elucidated. In this study, we revealed the complex and important roles of cuproptosis regulators and cuproptosis activity in tumors via a comprehensive analysis of multiomics data from more than 10,000 samples of 33 tumor types. We found that the cyclin-dependent kinase inhibitor 2A is the most frequently altered cuproptosis regulator, and the cuproptosis regulator expression is dysregulated in various tumors. Additionally, we developed a cuproptosis activity score to reflect the overall cuproptosis level. On the basis of the expression levels of cuproptosis regulators, tumors can be divided into two clusters with different cuproptosis activities and survival outcomes. Importantly, cuproptosis activity was found to be associated with the prognosis of multiple tumors and multiple tumor-related pathways, including fatty acid metabolism and remodeling of the tumor microenvironment. Furthermore, cuproptosis increased the sensitivity to multiple drugs and exhibited potential to predict the outcome of immunotherapy. We also comprehensively identified cuproptosis-related microRNAs, long noncoding RNAs, and transcription factors. We provided the code corresponding to the results of this study in GitHub (https://github.com/Changwuuu/Cuproptosis-pancancer.git) for reference. In summary, this study reveals important molecular and clinical characteristics of cuproptosis regulators and cuproptosis activity in tumors, and suggests the use of cuproptosis as a promising tumor therapeutic approach. This study provides an important reference point for future cuproptosis-related research.

Tumor antigens and immune subtypes of glioblastoma: the fundamentals of mRNA vaccine and individualized immunotherapy development.

Purpose: Glioblastoma (GBM) is the most common primary brain tumor in adults and is notorious for its lethality. Given its limited therapeutic measures and high heterogeneity, the development of new individualized therapies is important. mRNA vaccines have exhibited promising performance in a variety of solid tumors, those designed for glioblastoma (GBM) need further development. The aim of this study is to explore tumor antigens for the development of mRNA vaccines against GBM and to identify potential immune subtypes of GBM to identify the patients suitable for different immunotherapies. Methods: RNA-seq data and the clinical information of 143 GBM patients was extracted from the TCGA database; microarray data and the clinical information of 181 GBM patients was obtained from the REMBRANDT cohort. A GBM immunotherapy cohort of 17 patients was obtained from a previous literature. GEPIA2, cBioPortal, and TIMER2 were used to identify the potential tumor antigens. Immune subtypes and gene modules were identified using consensus clustering; immune landscape was constructed using graph-learning-based dimensionality reduction analysis. Results: Nine potential tumor antigens associated with poor prognosis and infiltration of antigen-presenting cells were identified in GBM: ADAMTSL4, COL6A1, CTSL, CYTH4, EGFLAM, LILRB2, MPZL2, SAA2, and LSP1. Four robust immune subtypes and seven functional gene modules were identified and validated in an independent cohort. Immune subtypes had different cellular and molecular characteristics, with IS1, an immune cold phenotype; IS2, an immune hot and immunosuppressive phenotype; IS3, a relatively immune cold phenotype, second only to IS1; IS4, having a moderate tumor immune microenvironment. Immune landscape revealed the immune distribution of the GBM patients. Additionally, the potential value of immune subtypes for individualized immunotherapy was demonstrated in a GBM immunotherapy cohort. Conclusions: ADAMTSL4, COL6A1, CTSL, CYTH4, EGFLAM, LILRB2, MPZL2, SAA2, and LSP1 are the candidate tumor antigens for mRNA vaccine development in GBM, and IS1 GBM patients are best suited for mRNA vaccination, IS2 patients are best suited for immune checkpoint inhibitor. This study provides a theoretical framework for GBM mRNA vaccine development and individualized immunotherapy strategies. Supplementary Information: The online version contains supplementary material available at 10.1186/s40537-022-00643-x.

A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma.

The role of homologous recombination deficiency (HRD) in lower grade glioma (LGG) has not been elucidated, and accurate prognostic prediction is also important for the treatment and management of LGG. The aim of this study was to construct an HRD-based risk model and to explore the immunological and molecular characteristics of this risk model. The HRD score threshold = 10 was determined from 506 LGG samples in The Cancer Genome Atlas cohort using the best cut-off value, and patients with high HRD scores had worse overall survival. A total of 251 HRD-related genes were identified by analyzing differentially expressed genes, 182 of which were associated with survival. A risk score model based on HRD-related genes was constructed using univariate Cox regression, least absolute shrinkage and selection operator regression, and stepwise regression, and patients were divided into high- and low-risk groups using the median risk score. High-risk patients had significantly worse overall survival than low-risk patients. The risk model had excellent predictive performance for overall survival in LGG and was found to be an independent risk factor. The prognostic value of the risk model was validated using an independent cohort. In addition, the risk score was associated with tumor mutation burden and immune cell infiltration in LGG. High-risk patients had higher HRD scores and "hot" tumor immune microenvironment, which could benefit from poly-ADP-ribose polymerase inhibitors and immune checkpoint inhibitors. Overall, this big data study determined the threshold of HRD score in LGG, identified HRD-related genes, developed a risk model based on HRD-related genes, and determined the molecular and immunological characteristics of the risk model. This provides potential new targets for future targeted therapies and facilitates the development of individualized immunotherapy to improve prognosis.

PLOD Family: A Novel Biomarker for Prognosis and Personalized Treatment in Soft Tissue Sarcoma.

Despite various treatment attempts, the heterogenous group of soft tissue sarcomata (STS) with more than 100 subtypes still shows poor outcomes. Therefore, effective biomarkers for prognosis prediction and personalized treatment are of high importance. The Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase (PLOD) gene family, which is related to multiple cancer entities, consists of three members which encode important enzymes for the formation of connective tissue. The relation to STS, however, has not yet been explored. In this study, data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to analyze the role of PLOD1-3 in STS. It was found that an overexpression of PLOD family members correlates with poor prognosis, which might be due to an increased infiltration of immune-related cells in the tumor microenvironment. In STS, the expression of PLOD genes could be a novel biomarker for prognosis and a personalized, more aggressive treatment in these patients.

Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase Family: Novel Prognostic Biomarkers and Tumor Microenvironment Regulators for Lower-Grade Glioma.

Lower-grade glioma (LGG) is a group of tumors arising from the cells of the central nervous system. Although various therapy interventions are used, the prognosis remains different. Novel biomarkers are needed for the prognosis of disease and novel therapeutic strategies in LGG. The procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family contains three members and is related to multiple cancers, yet it was not investigated in LGG. Data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) cohorts were used to analyze the role of PLOD in LGG. As the PLOD family is involved in processes, such as tumor formation and cancer metastasis, we focused on its relationship to the tumor microenvironment (TME) in LGG. A high expression of the PLOD family relates to poor prognosis and high infiltration of immune cells within the TME. The expression level of the PLOD family might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in LGG.

A Comprehensive Pan-Cancer Analysis for Pituitary Tumor-Transforming Gene 1.

Pituitary tumor-transforming gene 1 (PTTG1) encodes a multifunctional protein that is involved in many cellular processes. However, the potential role of PTTG1 in tumor formation and its prognostic function in human pan-cancer is still unknown. The analysis of gene alteration, PTTG1 expression, prognostic function, and PTTG1-related immune analysis in 33 types of tumors was performed based on various databases such as The Cancer Genome Atlas database, the Genotype-Tissue Expression database, and the Human Protein Atlas database. Additionally, PTTG1-related gene enrichment analysis was performed to investigate the potential relationship and possible molecular mechanisms between PTTG1 and tumors. Overexpression of PTTG1 may lead to tumor formation and poor prognosis in various tumors. Consequently, PTTG1 acts as a potential oncogene in most tumors. Additionally, PTTG1 is related to immune infiltration, immune checkpoints, tumor mutational burden, and microsatellite instability. Thus, PTTG1 could be potential biomarker for both prognosis and outcomes of tumor treatment and it could also be a promising target in tumor therapy.

Identification of Tumor Antigens and Immune Subtypes for the Development of mRNA Vaccines and Individualized Immunotherapy in Soft Tissue Sarcoma.

Soft tissue sarcomas (STS) are a rare disease with high recurrence rates and poor prognosis. Missing therapy options together with the high heterogeneity of this tumor type gives impetus to the development of individualized treatment approaches. This study identifies potential tumor antigens for the development of mRNA tumor vaccines for STS and explores potential immune subtypes, stratifying patients for immunotherapy. RNA-sequencing data and clinical information were extracted from 189 STS samples from The Cancer Genome Atlas (TCGA) and microarray data were extracted from 103 STS samples from the Gene Expression Omnibus (GEO). Potential tumor antigens were identified using cBioportal, the Oncomine database, and prognostic analyses. Consensus clustering was used to define immune subtypes and immune gene modules, and graph learning-based dimensionality reduction analysis was used to depict the immune landscape. Finally, four potential tumor antigens were identified, each related to prognosis and antigen-presenting cell infiltration in STS: HLTF, ITGA10, PLCG1, and TTC3. Six immune subtypes and six gene modules were defined and validated in an independent cohort. The different immune subtypes have different molecular, cellular, and clinical characteristics. The immune landscape of STS reveals the immunity-related distribution of patients and intra-cluster heterogeneity of immune subtypes. This study provides a theoretical framework for STS mRNA vaccine development and the selection of patients for vaccination, and provides a reference for promoting individualized immunotherapy.

Pyroptosis in glioblastoma: A crucial regulator of the tumour immune microenvironment and a predictor of prognosis.

Recent studies have shown that pyroptosis, an inflammatory form of cell death, has a dual role in tumorigenesis and tumour progression and affects the prognosis of patients; however, the role of pyroptosis in glioblastoma (GBM) is still unclear. In this study, based on GBM patients' data from two independent cohorts, we performed a comprehensive analysis of the expression and prognostic value of 33 pyroptosis-associated genes (PAGs) in GBM, as well as their role in the tumour immune microenvironment (TIME) of GBM. We identified 29 PAGs that were differentially expressed between GBM and normal brain tissue, 18 of which were upregulated in GBM tissue. Most of the 33 PAGs were strongly correlated with the levels of immune cell infiltration. Based on the 33 PAGs, the GBM samples can be divided into two clusters (C1-C2), with C1 having a 'hot' but immunosuppressive TIME and C2 having a 'cold' TIME, suggesting different immunotherapeutic responses in the two clusters. In addition, we identified four PAGs that were strongly associated with GBM prognosis and constructed a risk model based on these four PAGs. This risk model is an independent prognostic factor for GBM patients, and there is a different immune status between high- and low-risk groups. In conclusion, this study demonstrates that pyroptosis is closely associated with the prognosis and TIME of GBM and provides an important basis for further studies on the relationship between pyroptosis and GBM.

A Novel Four-Gene Prognostic Signature for Prediction of Survival in Patients with Soft Tissue Sarcoma.

Soft tissue sarcomas (STS), a group of rare malignant tumours with high tissue heterogeneity, still lack effective clinical stratification and prognostic models. Therefore, we conducted this study to establish a reliable prognostic gene signature. Using 189 STS patients' data from The Cancer Genome Atlas database, a four-gene signature including DHRS3, JRK, TARDBP and TTC3 was established. A risk score based on this gene signature was able to divide STS patients into a low-risk and a high-risk group. The latter had significantly worse overall survival (OS) and relapse free survival (RFS), and Cox regression analyses showed that the risk score is an independent prognostic factor. Nomograms containing the four-gene signature have also been established and have been verified through calibration curves. In addition, the predictive ability of this four-gene signature for STS metastasis free survival was verified in an independent cohort (309 STS patients from the Gene Expression Omnibus database). Finally, Gene Set Enrichment Analysis indicated that the four-gene signature may be related to some pathways associated with tumorigenesis, growth, and metastasis. In conclusion, our study establishes a novel four-gene signature and clinically feasible nomograms to predict the OS and RFS. This can help personalized treatment decisions, long-term patient management, and possible future development of targeted therapy.

A Human Pan-Cancer System Analysis of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 3 (PLOD3).

The overexpression of the enzymes involved in the degradation of procollagen lysine is correlated with various tumor entities. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) expression was found to be correlated to the progression and migration of cancer cells in gastric, lung and prostate cancer. Here, we analyzed the gene expression, protein expression, and the clinical parameters of survival across 33 cancers based on the Clinical Proteomic Tumor Analysis Consortium (CPTAC), function annotation of the mammalian genome 5 (FANTOM5), Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) databases. Genetic alteration, immune infiltration and relevant cellular pathways were analyzed in detail. PLOD3 expression negatively correlated with survival periods and the infiltration level of CD8+ T cells, but positively correlated to the infiltration of cancer associated fibroblasts in diverse cancers. Immunohistochemistry in colon carcinomas, glioblastomas, and soft tissue sarcomas further confirm PLOD 3 expression in human cancer tissue. Moreover, amplification and mutation accounted for the largest proportion in esophageal adenocarcinoma and uterine corpus endometrial carcinoma, respectively; the copy number alteration of PLOD3 appeared in all cancers from TCGA; and molecular mechanisms further proved the effect of PLOD3 on tumorigenesis. In particular, PLOD3 expression appears to have a tumor immunological effect, and is related to multiple immune cells. Furthermore, it is also associated with tumor mutation burden and microsatellite instability in various tumors. PLOD3 acts as an inducer of various cancers, and it could be a potential biomarker for prognosis and targeted treatment.

Integrative and Comprehensive Pancancer Analysis of Regulator of Chromatin Condensation 1 (RCC1).

Regulator of Chromatin Condensation 1 (RCC1) is the only known guanine nucleotide exchange factor that acts on the Ras-like G protein Ran and plays a key role in cell cycle regulation. Although there is growing evidence to support the relationship between RCC1 and cancer, detailed pancancer analyses have not yet been performed. In this genome database study, based on The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases, the potential role of RCC1 in 33 tumors' entities was explored. The results show that RCC1 is highly expressed in most human malignant neoplasms in contrast to healthy tissues. RCC1 expression is closely related to the prognosis of a broad variety of tumor patients. Enrichment analysis showed that some tumor-related pathways such as "cell cycle" and "RNA transport" were involved in the functional mechanism of RCC1. In particular, the conducted analysis reveals the relation of RCC1 to multiple immune checkpoint genes and suggests that the regulation of RCC1 is closely related to tumor infiltration of cancer-associated fibroblasts and CD8+ T cells. Coherent data demonstrate the association of RCC1 with the tumor mutation burden and microsatellite instability in various tumors. These findings provide new insights into the role of RCC1 in oncogenesis and tumor immunology in various tumors and indicate its potential as marker for therapy prognosis and targeted treatment strategies.

Prognostic value and immune cell infiltration of hypoxic phenotype-related gene signatures in glioblastoma microenvironment.

Glioblastoma (GBM) is a malignant intracranial tumour with the highest proportion and lethality. It is characterized by invasiveness and heterogeneity. However, the currently available therapies are not curative. As an essential environmental cue that maintains glioma stem cells, hypoxia is considered the cause of tumour resistance to chemotherapy and radiation. Growing evidence shows that immunotherapy focusing on the tumour microenvironment is an effective treatment for GBM; however, the current clinicopathological features cannot predict the response to immunotherapy and provide accurate guidance for immunotherapy. Based on the ESTIMATE algorithm, GBM cases of The Cancer Genome Atlas (TCGA) data set were classified into high- and low-immune/stromal score groups, and a four-gene tumour environment-related model was constructed. This model exhibited good efficiency at forecasting short- and long-term prognosis and could also act as an independent prognostic biomarker. Additionally, this model and four of its genes (CLECL5A, SERPING1, CHI3L1 and C1R) were found to be associated with immune cell infiltration, and further study demonstrated that these four genes might drive the hypoxic phenotype of perinecrotic GBM, which affects hypoxia-induced glioma stemness. Therefore, these might be important candidates for immunotherapy of GBM and deserve further exploration.

Multidisciplinary Therapy Managed Recurrent Glioblastoma in a BRAF-V600E Mutant Pregnant Female: A Case Report and Review of the Literature.

Background: Glioblastoma (GBM) is the most malignant intracranial tumor in adults. However, the overall management of GBM in pregnancy is rarely reported. How to balance the therapeutic benefits to the mother and risks to the fetus remains hugely challenging for clinicians. The application of specific targeting therapy combined with conventional treatment sheds light on a longer lifetime for the patients suffering from GBM. Case Presentation: We present a pregnant female at 20 weeks gestation diagnosed with GBM. Surgical resection was initially performed without adjuvant therapy, and the tumor recurred de novo 2 months later. A secondary craniotomy and cesarean section were performed simultaneously at 32 weeks gestation, both the patient and infant were survived. She was subsequently treated with traditional chemo-radiotherapy. No other identified genetic alterations indicating an optimistic prognosis were detected except for BRAF V600E mutation. Thus, the BRAF inhibitor was placed on her with achieving a good clinical outcome of more than 2-year survival without recurrence. Conclusion: Personalized multidisciplinary therapy should be considered when GBMs occur in pregnancy. Response to the therapy in this presenting case suggests that BRAF V600E mutation is a favorable biomarker for GBM. The mortality of GBM might be reduced through genetic testing and targeted treatment. However, more studies must be conducted to confirm our observation.