OsEIL2 balances rice immune responses against (hemi)biotrophic and necrotrophic pathogens via the salicylic acid and jasmonic acid synergism.

Plants typically activate distinct defense pathways against various pathogens. Heightened resistance to one pathogen often coincides with increased susceptibility to another pathogen. However, the underlying molecular basis of this antagonistic response remains unclear. Here, we demonstrate that mutants defective in the transcription factor ETHYLENE-INSENSITIVE 3-LIKE 2 (OsEIL2) exhibited enhanced resistance to the biotrophic bacterial pathogen Xanthomonas oryzae pv oryzae and to the hemibiotrophic fungal pathogen Magnaporthe oryzae, but enhanced susceptibility to the necrotrophic fungal pathogen Rhizoctonia solani. Furthermore, necrotroph-induced OsEIL2 binds to the promoter of OsWRKY67 with high affinity, leading to the upregulation of salicylic acid (SA)/jasmonic acid (JA) pathway genes and increased SA/JA levels, ultimately resulting in enhanced resistance. However, biotroph- and hemibiotroph-induced OsEIL2 targets OsERF083, resulting in the inhibition of SA/JA pathway genes and decreased SA/JA levels, ultimately leading to reduced resistance. Our findings unveil a previously uncharacterized defense mechanism wherein two distinct transcriptional regulatory modules differentially mediate immunity against pathogens with different lifestyles through the transcriptional reprogramming of phytohormone pathway genes.

Crosstalk of ferroptosis regulators and tumor immunity in pancreatic adenocarcinoma: novel perspective to mRNA vaccines and personalized immunotherapy.

Pancreatic adenocarcinoma (PAAD) is the eighth leading cause of cancer-related mortality that causes serious physical and mental burden to human. Reactive oxygen species accumulation and iron overload might enable ferroptosis-mediated cancer therapies. This study was to elusive novel ferroptosis regulator and its association with immune microenvironment and PD-L1 in PAAD. RNA-seq data and relevant information were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression. The R packages "ggplot2" and "pheatmap" were used to the expression of 20 ferroptosis regulators between PAAD and normal tissues. The R package "ConsensusClusterPlus", "survival", "survminer", "immunedeconv", and TIDE algorithm performed consensus clustering, overall survival, progression-free survival, disease free survival, immune infiltration level, and immunotherapy responses between cluster 1 and cluster 2. The prognostic value was confirmed by the Kaplan-Meier curves, receiver operating characteristic curve, univariate and multivariate cox regression, and nomogram. Moreover, the relationship of FANCD2 and immunity, drug sensitivity was investigated by R package "ggstatsplot", "immunedeconv", "ggalluvial" and "pRRophetic". Besides, the qRT-PCR, immunohistochemistry and western blotting detected the expression of FANCD2 in PAAD cell lines. Most ferroptosis regulators were up-regulated in PAAD, while the expression of LPCAT3, MT1G, and GLS2 was down-regulated in PAAD (P < 0.05), indicting there was a positively correlation among ferroptosis regulators. Based on clustering parameter, we identified cluster 1 and cluster 2, and cluster 2 had a better prognosis for patients with PAAD. The immune infiltration level of cluster 1 was higher in macrophage M1, myeloid dendritic cell, T cell CD4 + Th2, B cell, T cell CD8 + central memory, immune score, and microenvironment score than cluster 2 in PAAD. Moreover, FANCD2 was up-regulated in PAAD by public databases, immunohistochemistry, qRT-PCR and Western blotting, which had closely related to overall survival, immune microenvironment, and drug sensitivity. A novel crosstalk of ferroptosis exhibits a favourable prognostic performance and builds a robust theoretical foundation for mRNA vaccine and personalized immunotherapy. FANCD2 could be an effective for prognostic recognition, immune efficacy evaluation, and mRNA vaccine for patients with PAAD, providing a vital guidance for further study of regulating tumor immunity and vaccine development.

Dissection of pyroptosis-related prognostic signature and CASP6-mediated regulation in pancreatic adenocarcinoma: new sights to clinical decision-making.

Recent studies have indicated that pyroptosis may participate in the regulation of tumorigenesis and immune microenvironment. However, the role of pyroptosis-related genes (PRGs) in pancreatic adenocarcinoma (PAAD) remains unclear. Through multiple bioinformatics analysis, we constructed a prognostic gene model and competing endogenous RNA network. The correlation between PRGs and prognosis, immune infiltration, immune checkpoints, and tumor mutational burden was analyzed by Kaplan-Meier curve, univariate Cox, multivariate regression, and Spearman's analysis in PAAD patients. The qRT-PCR, Western blotting, CCK-8, Wound healing, and Transwell assay were applied to examine the role of CASP6 in PANC-1 cell. Thirty-one PRGs were upregulated in PAAD. Functional enrichment analysis revealed that the PRGs were mainly involved in pyroptosis, NOD-like receptor signaling pathway, and response to bacteria. We established a novel 4-gene signature related to PRGs for evaluating the prognosis of PAAD patients. Patients with PAAD in the low-risk group had a better prognosis than those in the high-risk group. The nomogram suggested that the 1-, 3-, and 5-years survival probability exhibited robust predictive performance. Significant correlation was observed between prognostic PRGs and immune infiltration, immune checkpoints, and tumor mutational burden. We first identified the potential competing endogenous RNA regulatory axis in PAAD: lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8. Moreover, knockdown of CASP6 dramatically inhibited the proliferation, migration, and invasion ability of PANC-1 cell in vitro. In conclusion, CASP6 could be a potential biomarker, promoting the occurrence and progression in PAAD. The lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8 regulatory axis plays an vital role in regulating the anti-tumor immune responses for PAAD.

Spotlights on ubiquitin-specific protease 12 (USP12) in diseases: from multifaceted roles to pathophysiological mechanisms.

Ubiquitination is one of the most significant post-translational modifications that regulate almost all physiological processes like cell proliferation, autophagy, apoptosis, and cell cycle progression. Contrary to ubiquitination, deubiquitination removes ubiquitin from targeted protein to maintain its stability and thus regulate cellular homeostasis. Ubiquitin-Specific Protease 12 (USP12) belongs to the biggest family of deubiquitinases named ubiquitin-specific proteases and has been reported to be correlated with various pathophysiological processes. In this review, we initially introduce the structure and biological functions of USP12 briefly and summarize multiple substrates of USP12 as well as the underlying mechanisms. Moreover, we discuss the influence of USP12 on tumorigenesis, tumor immune microenvironment (TME), disease, and related signaling pathways. This study also provides updated information on the roles and functions of USP12 in different types of cancers and other diseases, including prostate cancer, breast cancer, lung cancer, liver cancer, cardiac hypertrophy, multiple myeloma, and Huntington's disease. Generally, this review sums up the research advances of USP12 and discusses its potential clinical application value which deserves more exploration in the future.

NCAPG facilitates colorectal cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition by activating the Wnt/ß-catenin signaling pathway.

BACKGROUND: The condensation complex gene non-SMC condensin I complex subunit G(NCAPG), a cell cycle-associated condensin, is over-expressed in various cancers. However, its biological function in colorectal cancer (CRC) has yet to be deciphered. In this study, we investigated the role of NCAPG in CRC progression. METHODS: Tissues and cells were used to measure NCAPG expression levels and their association with clinicopathological characteristics. NCAPG silencing and overexpression in CRC cells were used to measure its effect on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) progression. In addition, mRNA, and protein expression levels of key EMT biomarkers were measured. The underlying mechanism of NCAPG modulating CRC progression was further explored using western blotting, co-immunoprecipitation (CO-IP), and immunofluorescence (IF) assays. RESULTS: NCAPG was over-expressed in CRC tissues and cell lines. High expression levels were associated with differentiation levels, lymph metastasis, and vascular invasion in patients. NCAPG silencing suppressed, while NCAPG overexpression promoted the proliferative, migration, and invasive capacity of HCT116 and SW480 cells. Mechanistically, we discovered that NCAPG participated in regulating the EMT process and the Wnt/ß-catenin signaling pathway to facilitate CRC invasion and metastasis. Additional experiments demonstrated that NCAPG activated the Wnt/ß-catenin signaling pathway by binding to ß-catenin in CRC cells. CONCLUSION: NCAPG acts as an oncogene involved in the development and progression of CRC by binding to ß-catenin to activate the Wnt/ß-catenin signaling pathway.

Comprehensive analyses reveal the carcinogenic and immunological roles of ANLN in human cancers.

BACKGROUND: Anillin (ANLN) is an actin-binding protein that is essential for cell division and contributes to cell growth and migration. Although previous studies have shown that ANLN is related to carcinogenesis, no pan-cancer analyses of ANLN have been reported. Accordingly, in this study, we evaluated the carcinogenic roles of ANLN in various cancer types using online databases. METHODS: We evaluated the potential carcinogenic roles of ANLN using TIMER2 and Gene Expression Omnibus databases with 33 types of cancers. We further investigated the associations of ANLN with patient prognosis, genetic alterations, phosphorylation levels, and immune infiltration in multiple cancers using GEPIA2, cBioPortal, UACLAN, and TIMER2 databases. Additionally, the potential functions of ANLN were explored using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Reverse transcription quantitative polymerase chain reaction and immunohistochemistry were used to determine ANLN mRNA and protein expression in colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC) cell lines. RESULTS: ANLN was overexpressed in various tumor tissues compared with corresponding normal tissues, and significant correlations between ANLN expression and patient prognosis, genetic alterations, phosphorylation levels, and immune infiltration were noted. Moreover, enrichment analysis suggested that ANLN functionally affected endocytosis, regulation of actin cytoskeleton, and oxytocin signaling pathways. Importantly, ANLN mRNA and protein expression levels were upregulated in gastrointestinal cancers, including CRC, GC, and HCC. CONCLUSIONS: Our findings suggested that ANLN participated in tumorigenesis and cancer progression and may have applications as a promising biomarker of immune infiltration and prognosis in various cancers.

Genome-wide association mapping for resistance to bacterial blight and bacterial leaf streak in rice.

MAIN CONCLUSION: Using genome-wide SNP association mapping, a total of 77 and 7 loci were identified for rice bacterial blight and bacterial leaf streak resistance, respectively, which may facilitate rice resistance improvement. Bacterial blight (BB) and bacterial leaf streak (BLS) caused by Gram-negative bacteria Xanthomonas oryzae pv. oryzae (Xoo) and X. oryzae pv. oryzicola (Xoc), respectively, are two economically important diseases negatively affecting rice production. To mine new sources of resistance, a set of rice germplasm collection consisting of 895 re-sequenced accessions from the 3000 Rice Genomes Project (3 K RGP) were screened for BB and BLS resistance under field conditions. Higher levels of BB resistance were observed in aus/boro subgroup, whereas the japonica, temperate japonica and tropical japonica subgroups possessed comparatively high levels of resistance to BLS. A genome-wide association study (GWAS) mined 77 genomic loci significantly associated with BB and 7 with BLS resistance. The phenotypic variance (R2) explained by these loci ranged from 0.4 to 30.2%. Among the loci, 7 for BB resistance were co-localized with known BB resistance genes and one for BLS resistance overlapped with a previously reported BLS resistance QTL. A search for the candidates in other novel loci revealed several defense-related genes that may be involved in resistance to BB and BLS. High levels of phenotypic resistance to BB or BLS could be attributed to the accumulation of the resistance (R) alleles at the associated loci, indicating their potential value in rice resistance breeding via gene pyramiding. The GWAS analysis validated the known genes underlying BB and BLS resistance and identified novel loci that could enrich the current resistance gene pool. The resources with strong resistance and significant SNPs identified in this study are potentially useful in breeding for BB and BLS resistance.

(-)-Epigallocatechin-3-gallate inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial-mesenchymal transition via NF-κB p65 inactivation.

The cancer stem cell (CSC) theory states that many types of cancer, including nasopharyngeal cancer (NPC), are initiated from and maintained by CSCs, which may be responsible for tumor relapse and resistance to therapy. It is imperative that nasopharyngeal cancer stem cells (NPCSCs) be specifically targeted to eradicate NPC and prevent recurrence. Epigallocatechin-3-gallate (EGCG) inhibits cancer progression by attenuating NF-κB p65 activity, which is upregulated in CSCs and plays an important role in epithelial-mesenchymal transition (EMT). The purpose of this study is to confirm the self-renewal and migration inhibitory effects of EGCG toward NPCSCs and to clarify its mechanism of activity. We enriched and characterized NPCSCs by collecting spheroid-derived cells grown in serum-free medium (SFM) and examined the effects of EGCG on the characteristics of NPCSCs and studied the underlying mechanisms using soft agar colony assays, transwell migration assays, reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis, immunofluorescence staining, and xenograft studies. NPC spheroids enriched from NPC cell lines acquired CSC traits and underwent EMT. EGCG inhibited the NPCSCs' self-renewal and migration and reversed EMT, and combined treatment with EGCG and cisplatin reduced the growth of CSC tumor xenografts. Moreover, EGCG inhibited NF-κB p65 activity by modulating the cellular localization of p65 and decreasing the transcriptional regulation of NF-κB p65 on Twist1 expression. NF-κB p65 is a novel therapeutic target in NPCSCs, and the inhibition of activated NF-κB p65 in CSCs by EGCG may offer an effective treatment for NPC.

How CLSPN could demystify its prognostic value and potential molecular mechanism for hepatocellular carcinoma: A crosstalk study.

BACKGROUND & AIMS: CLSPN, a critical component of the S-phase checkpoint in response to DNA replication stress, has been implicated in the pathogenesis of multiple tumor types. The rising incidence of hepatocellular carcinoma (HCC) poses a significant challenge to global public health. Despite this, the specific functions of CLSPN in the development of HCC remain poorly understood. METHODS: We systematically evaluated the expression of CLSPN, prognosis and immune infiltration in patients with HCC and identified a competing endogenous RNA (ceRNA) network by using public database. The RT-qPCR, western blot, CCK8, transwell, flow cytometry, animal experiments, proteasome inhibition experiment, Co-IP assay and mass spectrometry were applied to explore its biological functions, post-transcriptional modifications and potential molecular mechanisms of CLSPN in HCC. RESULTS: We verified the expression of CLSPN, and its high expression is an independent prognostic factor in HCC. The expression of CLSPN is also associated with the immune microenvironment of HCC. CLSPN silencing inhibited the proliferation, migration, invasion and cell cycle progression of HCC cells. We established a PSMA3-AS1/hsa-miR-101-3p/CLSPN regulator axis in HCC. CLSPN was influenced by ubiquitination and was involved in the Wnt/ß-catenin pathway to regulate HCC progression. CONCLUSIONS: It was the first time to comprehensively discover and identify the expression, prognosis, immunotherapy, RNAs regulator, posttranscriptional modification, and molecular mechanisms of CLSPN in HCC. These novel insights have the potential to expedite the development of personalized treatment strategies and translational medicine approaches for HCC patients.

Ubiquitin specific peptidase 3: an emerging deubiquitinase that regulates physiology and diseases.

Proteins are the keystone for the execution of various life activities, and the maintenance of protein normalization is crucial for organisms. Ubiquitination, as a post-transcriptional modification, is widely present in organisms, and it relies on the sophisticated ubiquitin-proteasome (UPS) system that controls protein quality and modulates protein lifespan. Deubiquitinases (DUBs) counteract ubiquitination and are essential for the maintenance of homeostasis. Ubiquitin specific peptidase 3 (USP3) is a member of the DUBs that has received increasing attention in recent years. USP3 is a novel chromatin modifier that tightly regulates the DNA damage response (DDR) and maintains genome integrity. Meanwhile, USP3 acts as a key regulator of inflammatory vesicles and sustains the normal operation of the innate immune system. In addition, USP3 is aberrantly expressed in a wide range of cancers, such as gastric cancer, glioblastoma and neuroblastoma, implicating that USP3 could be an effective target for targeted therapies. In this review, we retrace all the current researches of USP3, describe the structure of USP3, elucidate its functions in DNA damage, immune and inflammatory responses and the cell cycle, and summarize the important role of USP3 in multiple cancers and diseases.

A review: targeting UBR5 domains to mediate emerging roles and mechanisms - chance or necessity?

Ubiquitinases are known to catalyze ubiquitin chains on target proteins to regulate various physiological functions like cell proliferation, autophagy, apoptosis, and cell cycle progression. As a member of E3 ligase, ubiquitin protein ligase E3 component n-recognin 5 (UBR5) belongs to the HECT E3 ligase and has been reported to be correlated with various pathophysiological processes. In this review, the authors give a comprehensive insight into the structure and function of UBR5. The authors discuss the specific domains of UBR5 and explore their biological functions separately. Furthermore, the authors describe the involvement of UBR5 in different pathophysiological conditions, including immune response, virus infection, DNA damage response, and protein quality control. Moreover, the authors provide a thorough summary of the important roles and regulatory mechanisms of UBR5 in cancers and other diseases. On the whole, investigating the domains and functions of UBR5, elucidating the underlying mechanisms of UBR5 with various substrates in detail may provide new theoretical basis for the treatment of diseases, including cancers, which could improve future studies to construct novel UBR5-targeted therapy strategies.

The F-box protein OsFBX156 positively regulates rice defence against the blast fungus Magnaporthe oryzae by mediating ubiquitination-dependent degradation of OsHSP71.1.

F-box protein is a subunit of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which plays a critical role in regulating different pathways in plant immunity. In this study, we identified the rice (Oryza sativa) F-box protein OsFBX156, which targets the heat shock protein 70 (OsHSP71.1) to regulate resistance to the rice blast fungus Magnaporthe oryzae. Overexpression of OsFBX156 or knockout of OsHSP71.1 in rice resulted in the elevation of pathogenesis-related (PR) genes and an induction burst of reactive oxygen species (ROS) after flg22 and chitin treatments, thereby enhancing resistance to M. oryzae. Furthermore, OsFBX156 can promote the degradation of OsHSP71.1 through the 26S proteasome pathway. This study sheds lights on a novel mechanism wherein the F-box protein OsFBX156 targets OsHSP71.1 for degradation to promote ROS production and PR gene expression, thereby positively regulating rice innate immunity.

APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

Exosomal transfer of miR-548aq-3p confers cisplatin resistance via MED12 downregulation in epithelial ovarian cancer.

OBJECTIVE: The RNA polymerase II mediator complex subunit 12 (MED12) is an important factor for chemotherapy sensitivity. We explored the roles of exosomal transfer of carcinogenic microRNAs (miRNAs) in MED12 regulation and cisplatin resistance of ovarian cancer cells. In this study, the correlation between MED12 expression and cisplatin resistance was analyzed in ovarian cancer cells. The molecular regulation of MED12 by exosomal miR-548aq-3p was investigated by bioinformatics analysis and luciferase reporter assays. Further clinical significance of miR-548aq was assessed with TCGA data. We identified decreased MED12 expression in cisplatin-resistance of ovarian cancer cells. More importantly, coculture with cisplatin-resistant cells attenuated cisplatin sensitivity of parental ovarian cancer cells, as well as reduced MED12 expression to a large extent. Further bioinformatic analysis identified that exosomal miR-548aq-3p was correlated with MED12 transcriptional regulation in ovarian cancer cells. Luciferase reporter assays demonstrated that miR-548aq-3p down-regulated MED12 expression. miR-548aq-3p overexpression enhanced cell survival and proliferation of ovarian cancer cells with cisplatin treatment, while miR-548aq-3p inhibition induced cell apoptosis of cisplatin-resistant cells. Further clinical analysis indicated that miR-548aq was correlated with lower MED12 expression. More importantly, miR-548aq expression was a detrimental factor in the disease progression of ovarian cancer patients. In conclusion, we found that miR-548aq-3p contributed to cisplatin chemotherapy resistance of ovarian cancer cells through MED12 downregulation. Our study supported miR-548aq-3p as a promising therapeutic target for improving chemotherapy sensitivity of ovarian cancer.

N6-methyladenosine with immune infiltration and PD-L1 in hepatocellular carcinoma: novel perspective to personalized diagnosis and treatment.

Background: Increasing evidence elucidated N6-methyladenosine (m6A) dysregulation participated in regulating RNA maturation, stability, and translation. This study aimed to demystify the crosstalk between m6A regulators and the immune microenvironment, providing a potential therapeutic target for patients with hepatocellular carcinoma (HCC). Methods: Totals of 371 HCC and 50 normal patients were included in this study. GSE121248 and GSE40367 datasets were used to validate the expression of HNRNPC. The R package "ConsensusClusterPlus" was performed to screen consensus clustering types based on the expression of m6A regulators in HCC. The R package "pheatmap", "immunedeconv", "survival", "survminer" and "RMS" were applied to investigate the expression, immunity, overall survival, and clinical application in different clusters and expression groups. Comprehensive analysis of HNRNPC in pan-cancer was conducted by TIMER2 database. Besides, HNRNPC mRNA and protein expression were verified by qRT-PCR and immunohistochemistry analysis. Results: Most of m6A regulators were over-expressed excerpt for ZC3H13 in HCC. Three independent clusters were screened based on m6A regulators expression, and the cluster 2 had a favorable prognosis in HCC. Then, the cluster 2 was positively expression in macrophage, hematopoietic stem cell, endothelial cell, and stroma score, while negatively in T cell CD4+ memory and mast cell. We identified HNRNPC was an independent prognostic factor in HCC, and nomogram performed superior application value for clinical decision making. Moreover, PD-L1 was significantly up-regulated in HCC tissues, cluster 1, and cluster 3, and we found PD-L1 expression was positively correlated with HNRNPC. Patients with HCC in high-expression groups was associated with tumor-promoting cells. Besides, HNRNPC was correlated with prognosis, TMB, and immune checkpoints in cancers. Particularly, the experiments confirmed that HNRNPC was positively expression in HCC cells and tissues. Conclusion: The m6A regulators play irreplaceable roles in prognosis and immune infiltration in HCC, and the relationship of HNRNPC and PD-L1 possesses a promising direction for therapeutic targets of immunotherapy response. Exploration of m6A regulators pattern could be build the prognostic stratification of individual patients and move toward to personalized treatment.

A bibliometric and visualized research on global trends of immune checkpoint inhibitors related complications in melanoma, 2011-2021.

Background: Melanoma is a malignant tumor that originates from the canceration of melanocytes with a high rate of invasiveness and lethality. Immune escape has been regarded as an important mechanism for tumor development, while the treatment of immune checkpoint inhibitors (ICIs) is beneficial in restoring and enhancing the body's anti-tumor immune response to kill tumor cells. To date, ICIs therapy has achieved remarkable efficacy in treating melanoma patients. Despite the significant clinical benefits of ICIs, multiple complications such as rashes, thyroiditis, and colitis occur in melanoma patients. In this study, we aim to explore the development process and trends in the field of ICIs-related complications in melanoma, analyze current hot topics, and predict future research directions. Methods: We screened the most relevant literatures on ICIs-related complications in melanoma from 2011 to 2021 in the Web of Science Core Collection (WoSCC). Using VOSviewer, CiteSpace and R language packages, we analyzed the research trends in this field. Results: A total of 1,087 articles were screened, and the USA had the highest number of publications (publications = 454, citations = 60,483), followed by Germany (publications = 155, citations = 27,743) and Italy (publications = 139, citations = 27,837). The Memorial Sloan Kettering Cancer Center had the most publications, but the Angeles Clinic and Research Institute had the highest average citation rate. Lancet oncology (IF, 2021 = 54.43) was the most prominent of all journals in terms of average citation rate. Reference and keyword cluster analysis revealed that anti-tumor efficacy, adjuvant treatment, clinical response, clinical outcome, etc. were the hotspots and trends of research in recent years. Conclusions: This study offers a comprehensive summary and analysis of global research trends on ICIs-related complications in melanoma. Over the past decade, there has been a significant increase in the number of publications on this topic. However, the safety and benefits of retreatment after the recovery of ICIs-related complications remain unknown. Therefore,the establishment of related prediction models, as well as the immunotherapy of melanoma with ICIs in combination with other adjuvant therapies, are future research hotspots.

Characterization of SHCBP1 to prognosis and immunological landscape in pan-cancer: novel insights to biomarker and therapeutic targets.

BACKGROUND: Previous studies have revealed the significant roles of SHC SH2 domain-binding protein 1 (SHCBP1) in occurrence and progression of cancers, but there is no pan-cancer analysis of SHCBP1. METHODS: In this study, we explored the potential carcinogenic role of SHCBP1 across 33 tumors from the TCGA and GTEx databases. We investigated SHCBP1 expression, prognosis, genetic alterations, tumor mutational burden (TMB) score, microsatellite instability (MSI) and tumor microenvironment from TIMER2, GEPIA2, UALCAN and cBioPortal databases. Moreover, the cellular functions and potential mechanisms were evaluated by GO and KEGG analysis. Besides, the mRNA expression of SHCBP1 was examined using qRT-PCR assay in gastrointestinal cancers. RESULTS: SHCBP1 was significantly upregulated in various cancers, and apparent relationship existed between SHCBP1 and survival prognosis in patients. The TMB, MSI, and tumor microenvironment analysis indicated that SHCBP1 was closely related to immune checkpoints, immune targets, as well as CD4+ naive T cell, CD8+ T cell, and neutrophil. Moreover, the cellular functions of SHCBP1 were mainly in regulating cell cycle motor protein activity. In addition, we validated that SHCBP1 mRNA expression was over-expressed in gastrointestinal cancers. CONCLUSIONS: This study was the first to systematically determine the prognostic value of SHCBP1, providing a forward-looking perspective on immunotherapy and cellular processes in pan-cancer.

GLTP Is a Potential Prognostic Biomarker and Correlates with Immunotherapy Efficacy in Cervical Cancer.

Cervical cancer (CC) is the fourth most commonly diagnosed cancer in women worldwide. The prognosis of CC patients remains poor. The objective of our study was to explore the potential of glycolipid transfer protein (GLTP) in predicting the prognosis of CC and patients' response to immunotherapy. The expression of GLTP was determined using TCGA and GEO datasets. The prognostic value of GLTP in CC patients was analyzed using Kaplan-Meier analysis and multivariate analysis. The relationships between BTBD10 and immunological checkpoints, immune checkpoint genes, and ferroptosis-related genes were analyzed to explore the impact of GLTP on CC immunotherapy. According to the dysregulated expressions of BTBD10, the IC50 distribution of various targeted medicines was studied. In this study, we found that GLTP expression was distinctly upregulated in CC specimens. However, Kaplan-Meier assays showed that CC patients with low GLTP expressions tended to exhibit a shorter overall survival. Importantly, multivariate assays revealed that GLTP expression was an independent prognostic factor for CC patients. Moreover, we observed that GLTP expression was related to CD4+ T cells, macrophages, and dendritic cells (DCs). Meanwhile, GLTP expressions were associated with those of immune checkpoints, ferroptosis-related genes, and m6A-related genes. The IC50 of Cisplatin, Docetaxel, and Paclitaxel was lower in the high-GLTP-expressing group. Taken together, GLTP was expected to be a prognostic and immunotherapeutic marker for CC.

Deciphering a mitochondria-related signature to supervise prognosis and immunotherapy in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a major public health problem in humans. The imbalance of mitochondrial function has been discovered to be closely related to the development of cancer recently. However, the role of mitochondrial-related genes in HCC remains unclear. Methods: The RNA-sequencing profiles and patient information of 365 samples were derived from the Cancer Genome Atlas (TCGA) dataset. The mitochondria-related prognostic model was established by univariate Cox regression analysis and LASSO Cox regression analysis. We further determined the differences in immunity and drug sensitivity between low- and high-risk groups. Validation data were obtained from the International Cancer Genome Consortium (ICGC) dataset of patients with HCC. The protein and mRNA expression of six mitochondria-related genes in tissues and cell lines was verified by immunohistochemistry and qRT-PCR. Results: The six mitochondria-related gene signature was constructed for better prognosis forecasting and immunity, based on which patients were divided into high-risk and low-risk groups. The ROC curve, nomogram, and calibration curve exhibited admirable clinical predictive performance of the model. The risk score was associated with clinicopathological characteristics and proved to be an independent prognostic factor in patients with HCC. The above results were verified in the ICGC validation cohort. Compared with normal tissues and cell lines, the protein and mRNA expression of six mitochondria-related genes was upregulated in HCC tissues and cell lines. Conclusion: The signature could be an independent factor that supervises the immunotherapy response of HCC patients and possess vital guidance value for clinical diagnosis and treatment.

Glycosylation-related molecular subtypes and risk score of hepatocellular carcinoma: Novel insights to clinical decision-making.

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer deaths worldwide, seriously affecting human community health and care. Emerging evidence has shown that aberrant glycosylation is associated with tumor progression and metastasis. However, the role of glycosylation-related genes in HCC has notbeen reported. Methods: Weighted gene coexpression network analysis and non-negative matrix factorization analysis were applied to identify functional modules and molecularm subtypes in HCC. The least absolute shrinkage and selection operator Cox regression was used to construct the glycosylation-related signature. The independent prognostic value of the risk model was confirmed and validated by systematic techniques, including principal component analysis, T-distributed random neighbor embedding analysis, Kaplan-Meier survival analysis, the ROC curve, multivariate Cox regression, the nomogram, and the calibration curve. The single-sample gene set enrichment analysis, gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were evaluated by the immune microenvironment and potential biological processes. The quantitative real-time polymerase chain reaction and immunohistochemistry analysis were used to verify the expression of five genes. Results: We identified the glycosylation-related genes with bioinformatics analysis to construct and validate a five-gene signature for the prognosis of HCC patients. Patients with HCC in the high-risk group had a worse prognosis. The risk score could be an independent factor and was associated with clinical features, such as the grade and stage. The nomogram exhibited an accurate score that included the risk score and clinical parameters. The infiltration levels of antitumor cells were upregulated in the low-risk group, including B_cells, Mast_cells, neutrophils, NK_cells, and T_helper_cells. Moreover, glycosylation was more sensitive to immunotherapy, and may play a critical role in the metabolic processes of HCC, such as bile acid metabolism and fatty acid metabolism. In addition, the five-gene messenger RNA (mRNA) and protein expression were overexpressed in HCC cells and tissues. Conclusions: The glycosylation-related signature is effective for prognostic recognition, immune efficacy evaluation, and substance metabolism in HCC, providing a novel insight for therapeutic target prediction and clinical decision-making.