Establishment of a novel efferocytosis potential index predicts prognosis and immunotherapy response in cancers.

The biological function and prognostic value of efferocytosis in cancer remains unclear. In this study, we systematically analysed the expression profiles and genetic variations of 50 efferocytosis-related regulator genes in 33 cancer types. Using data from The Cancer Genome Atlas, we established an efferocytosis potential index (EPI) model to represent the efferocytosis level in each cancer type. The relationship between the EPI and prognosis, immune-related molecules, specific pathways, and drug sensitivity was determined. We found that efferocytosis regulator genes were abnormally expressed in cancer tissue, perhaps owing to copy number variations, gene alterations, and DNA methylation. For the most part, the EPI was higher in tumour vs. normal tissues. In most of the 33 cancer types, it positively correlated with cell death- and immune-related pathway enrichment, the tumour microenvironment, immune infiltration, and drug sensitivity. For specific cancers, a high EPI may be a prognostic risk factor and, in patients treated receiving immune checkpoint therapy, a predictor of poor prognosis. Our study reveals the biological functions of efferocytosis-related regulator genes in distinct cancers and highlights the potential of efferocytosis intervention in cancer therapy.

Pan-cancer analysis of homeodomain-containing gene C10 and its carcinogenesis in lung adenocarcinoma.

We found elevated homeodomain-containing gene C10 (HOXC10) showed dual roles in cancers' prognosis. Some signal pathways associated with tumor were totally positively enriched in HOXC10 for whole cancers. On the contrary, Notch signaling, Wnt-beta catenin signaling, myogenesis, and Hedgehog signaling were almost negatively enriched in HOXC10. Some pathways showed dual roles such as Kras signaling, interferon gram and alpha response, IL6/JAK/STAT3, IL2/STAT5 signaling. HOXC10 was associated with tumor mutation burden and microsatellite instability. HOXC10 also was associated with tumor microenvironment and immune status. HOXC10 was negatively associated with immune score in most cancers except colon adenocarcinoma. The correlations of HOXC10 with immune-related genes presented dual roles in different cancers. Results from our clinical samples indicated that HOXC10 was an independent predictor for distant metastasis-free survival in lung adenocarcinoma (LUAD). Notably, the high levels of HOXC10 were positively correlated with the expression of angiogenic markers, vascular endothelial growth factor and microvessel density, and the number of CTC clusters. Our results demonstrated that aberrant expression happened in most cancers, which also affected the clinical prognosis and involved in progression via multiple signal pathways cancers. HOXC10 overexpression plays an important role in the aggression and metastasis in LUAD, which indicated a potential therapeutic target and an independent factor for the prognosis for LUAD patients.

Integrative analyses reveal biological function and prognostic role of m7G methylation regulators in high-grade glioma.

Based on 29 m7G regulators, glioma patients were categorized into three groups using data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets. Distinct characteristics were observed in immune cell infiltration, functional enrichment, and clinical prognosis for every glioma subtype. Analyzing the differentially expressed genes (DEGs) confirmed the distinction among the three m7G clusters. A predictive tool for overall survival (OS) in high-grade glioma patients was developed and confirmed, consisting of 13 m7G regulators forming a prognostic signature. Elevated m7G levels were found to be associated with increased tumor mutation burden and immune activation, indicating a tumor microenvironment characterized by inflammation and a lower overall survival rate. In contrast, reduced m7G scores were linked to a deficiency in immune infiltration, a low burden of mutations, and a non-inflamed phenotype, suggesting a more positive clinical outlook. Additionally, the m7G risk scores were found to impact chemotherapy sensitivity. The m7G predictive pattern shows potential as a marker for the overall survival of patients with high-grade glioma. By significantly improving our comprehension of the functional role of m7G regulators in the advancement of glioma and their impact on clinical results, this study offers valuable perspectives for precision therapy in the management of high-grade glioma.

Prognostic analysis and nomogram construction for older patients with IDH-wild-type glioblastoma.

As many countries face an ageing population, the number of older patients with glioblastoma (GB) is increasing. Thus, there is an urgent need for prognostic models to aid in treatment decision-making and life planning. A total of 98 patients with isocitrate dehydrogenase (IDH)-wild-type GB aged ≥65 years were analysed from January 2012 to January 2020. Independent prognostic factors were identified by prognostic analysis. Using the independent prognostic factors for overall survival (OS), a nomogram was constructed by R software to predict the prognosis of older patients with IDH-wild-type GB. The concordance index (C-index) and receiver operating characteristic (ROC) curve were used to assess model discrimination, and the calibration curve was used to assess model calibration. Prognostic analysis showed that the extent of resection (EOR), adjusted Charlson comorbidity index (ACCI), O6-methylguanine-DNA methyltransferase (MGMT) methylation status, postoperative radiotherapy, and postoperative temozolomide (TMZ) chemotherapy were independent prognostic factors for OS. MGMT methylation status and subventricular zone (SVZ) involvement were independent prognostic factors for progression-free survival (PFS). A nomogram was constructed based on EOR, ACCI, MGMT methylation status, postoperative radiotherapy and postoperative TMZ chemotherapy to predict the 6-month, 12-month and 18-month OS of older patients with IDH-wild-type GB. The C-index of the nomogram was 0.72, and the ROC curves showed that the areas under the curve (AUCs) at 6, 12 and 18 months were 0.874, 0.739 and 0.779, respectively. The calibration plots showed that the nomogram was in good agreement with the actual observations in predicting the OS of older patients with IDH-wild-type GB. Older patients with IDH-wild-type GB can benefit from gross total resection (GTR), postoperative radiotherapy and postoperative TMZ chemotherapy. A high ACCI score and MGMT nonmethylation are poor prognostic factors. We constructed a nomogram including the ACCI to facilitate clinical decision-making and follow-up interval selection.

Synthesis, characterization and anti-breast cancer activities of stachydrine derivatives.

Stachydrine is a hydrophilic quaternary amine salt with good antitumor effect, but its application is limited due to its rapid metabolism and low bioavailability. We synthesized and evaluated nine prodrugs of stachydrine, which showed suitable hydrophobicity (CLogP: -2.58-4.78, vs SS-0: -3.32) and better in vitro anticancer activity (IC50: 0.34 µM-14.03 mM, vs SS-0: 38.97 mM-147.19 mM) in comparison with stachydrine. Among them, SS-12, SS-16 and SS-18 are the most effective compounds against 4T1 cells, and the IC50 is 2.15-24.14 µM. Especially, compared with stachydrine, SS-12 significantly blocked the cell cycle in the G0/G1 phase, reduced the mitochondrial membrane potential, and induced the apoptosis of 4T1 cells through mitochondria pathway, which increased the expressions of Bax and cleaved caspase-3 protein, decrease the expression of Bcl-2. The pharmacokinetics of SS-12 showed a rational bioavailability (79.6%), and a longer retention time (T1/2 = 7.62 h) than that of stachydrine (T1/2 ≈ 1.16 h) in rats. Compared with stachydrine, SS-12 significantly enhanced the anticancer efficacy (56.32% of tumor-inhibition rates, vs SS-0: 3.89%), meanwhile, ameliorated the tumor-induced organ damage in mice. Therefore, SS-12 may be a promising prodrug of stachydrine against breast cancer.

Pan-cancer analysis identifies the correlations of Thymosin Beta 10 with predicting prognosis and immunotherapy response.

Introduction: The biological function and prognosis roles of thymosin ß(TMSB) 10 are still unclear in pan-cancer. Methods: We retrieved The Cancer Genome Atlas and Genotype-tissue expression datasets to obtain the difference of TMSB10 expression between pan-cancer and normal tissues, and analyzed the biological function and prognosis role of TMSB10 in pan-cancer by using cBioPortal Webtool. Results: The expression of TMSB10 in tumor tissues was significantly higher than normal tissues, and showed the potential ability to predict the prognosis of patients in Pan-cancer. It was found that TMSB10 was significantly correlated with tumor microenvironment, immune cell infiltration and immune regulatory factor expression. TMSB10 is involved in the regulation of cellular signal transduction pathways in a variety of tumors, thereby mediating the occurrence of tumor cell invasion and metastasis. Finally, TMSB10 can not only effectively predict the anti-PD-L1 treatment response of cancer patients, but also be used as an important indicator to evaluate the sensitivity of chemotherapy. In vitro, low expression of TMSB10 inhibited clonogenic formation ability, invasion, and migration in glioma cells. Furthermore, TMSB10 may involve glioma immune regulation progression by promoting PD-L1 expression levels via activating STAT3 signaling pathway. Conclusions: Our results show that TMSB10 is abnormally expressed in tumor tissues, which may be related to the infiltration of immune cells in the tumor microenvironment. Clinically, TMSB10 is not only an effective prognostic factor for predicting the clinical treatment outcome of cancer patients, but also a promising biomarker for predicting the effect of tumor immune checkpoint inhibitors (ICIs) and chemotherapy in some cancers.

FDX1 serves as a prognostic biomarker and promotes glioma progression by regulating the immune response.

The present study investigates the prognostic value of the FDX1 gene and its association with immune infiltration in gliomas. Gene expression profiles and corresponding clinical parameters of glioma patients were obtained from the Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. In vitro experiments were also performed to validate its impact on malignant phenotypes of glioma cells. Kaplan-Meier analysis demonstrated that high FDX1 expression was associated with poor prognosis in glioma. Function and pathway enrichment for FDX1 predominantly demonstrated immunomodulatory function. In addition, the high-FDX1 expression group had higher Estimation of Stromal and Immune cells in malignant tumor tissues using Expression data, stromal, and immune scores (p<0.001). On evaluation of immunotherapy response, TIDE and dysfunction scores were higher in the low-FDX1 group, while the exclusion score demonstrated an opposite trend. In vitro tests showed that FDX1 silencing-induced inhibition of cell invasion and migration inactivated the nucleotide oligomerization domain (NOD)-like receptor signaling pathway by regulating PD-L1 expression. Notably, NOD1 expression was reversed in FDX1-knockdown cells after treatment with NOD1 agonists. In conclusion, FDX1 may play an important role in the diagnosis and treatment of gliomas. Regulating its expression may therefore help improve immunotherapy for these tumors.

Integrative analyses reveal prognostic and immunogenic characteristics of m7G methylation regulators in patients with glioma.

OBJECTIVES: The expression profiles, biological mechanisms, and clinical relevance of m7G regulators in glioma were studied in this research. METHODS: Based on the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets, glioma patients, can be categorized into three groups according to 29 m7G regulators, and different subtypes of glioma show different immune cell infiltration characteristics, function enrichment, and clinical prognosis. Three gene clusters were confirmed by utilizing the differentially expressed genes (DEGs) across the three m7G clusters. RESULTS: A prognostic signature based on 12 m7G regulators was established and validated, producing an effective tool for predicting overall survival (OS) in glioma patients. High m7G scores indicated elevated tumor mutation burden and activation of immunity, suggesting an inflamed tumor microenvironment phenotype with poor overall survival. Low m7G scores characterized by a lack of immune infiltration and low mutation burden indicated a non-inflamed phenotype with a favorable clinical prognosis. It was also found that the m7G risk scores can affect chemotherapy sensitivity and prognosis of patients who received immunotherapy. The hub gene EIF4E1B of m7G regulators can inhibit the in vitro progression of glioma cells by regulating PD-L1 expression through p53 signaling pathway-related inactivation. CONCLUSIONS: The m7G prognostic signature can be a biomarker of the overall survival of patients with glioma. An initial in-vitro experiment suggested the potential biological mechanisms of immune regulation, with m7G regulators affecting glioma progression by modulating immune responses. The present research provides a better understanding of how m7G regulators function in glioma progression as well as the impact on clinical outcomes, which can provide new insights that might be beneficial for precision therapy of glioma.

A novel peptide protects against diet-induced obesity by suppressing appetite and modulating the gut microbiota.

OBJECTIVE: The obesity epidemic and its metabolic complications continue to be a major global public health threat with limited effective treatments, especially drugs that can be taken orally. Peptides are a promising class of molecules that have gained increased interest for their applications in medicine and biotechnology. In this study, we focused on looking for peptides that can be administrated orally to treat obesity and exploring its mechanisms. DESIGN: Here, a 9-amino-acid peptide named D3 was designed and administered orally to germ-free (GF) mice and wild-type (WT) mice, rats and macaques. The effects of D3 on body weight and other basal metabolic parameters were evaluated. The effects of D3 on gut microbiota were evaluated using 16S rRNA amplicon sequencing. To identify and confirm the mechanisms of D3, transcriptome analysis of ileum and molecular approaches on three animal models were performed. RESULTS: A significant body weight reduction was observed both in WT (12%) and GF (9%) mice treated with D3. D3 ameliorated leptin resistance and upregulated the expression of uroguanylin (UGN), which suppresses appetite via the UGN-GUCY2C endocrine axis. Similar effects were also found in diet-induced obese rat and macaque models. Furthermore, the abundance of intestinal Akkermansia muciniphila increased about 100 times through the IFNγ-Irgm1 axis after D3 treatment, which may further inhibit fat absorption by downregulating Cd36. CONCLUSION: Our results indicated that D3 is a novel drug candidate for counteracting diet-induced obesity as a non-toxic and bioactive peptide. Targeting the UGN-GUCY2C endocrine axis may represent a therapeutic strategy for the treatment of obesity.

Molecular subtypes of cuproptosis regulators and their correlation with clinical prognosis and immune response in glioma.

Cuproptosis is a newly described form of cell death. However, nothing is known about the roles of cuproptosis regulators in glioma. First, we explored the characteristics of cuproptosis molecular subtypes and relevant tumor microenvironment (TME) immune cell infiltration patterns in glioma. Using unsupervised clustering analysis, we identified two cuproptosis subtypes and three gene clusters that exhibited different clinical characteristics and TME cell infiltration patterns. Then, we developed and validated a cuproptosis-related prognostic model for predicting the overall survival of glioma patients. We established a risk score tool based on a nomogram to assess the clinical applicability of the cuproptosis model. A high cuproptosis risk score with high immune cell infiltration level, tumor mutation burden, gene alterations, and immunity activation had an unfavorable overall survival. Next, we identified possible competing endogenous ribonucleic acid regulatory networks based on significantly differentially expressed genes between high-risk and low-risk groups and screened several candidate small molecular compounds that may improve chemotherapy. Data from IMvigor and GSE78200 showed that the cuproptosis score affected the prognosis of patients who received immunotherapy. Our study indicated that cuproptosis regulators are involved in TME immune infiltration and impact the clinical prognosis in glioma. It is necessary for clinical practice to develop different therapeutic strategies according to the different phenotypes associated with immune response. The present findings provide new insight for improving immunotherapy strategies and individualized treatment in glioma.

Molecular subtypes based on cuproptosis regulators and immune infiltration in kidney renal clear cell carcinoma.

Copper toxicity involves the destruction of mitochondrial metabolic enzymes, triggering an unusual mechanism of cell death called cuproptosis, which proposes a novel approach using copper toxicity to treat cancer. However, the biological function of cuproptosis has not been fully elucidated in kidney renal clear cell carcinoma (KIRC). Using the expression profile of 13 cuproptosis regulators, we first identified two molecular subtypes related to cuproptosis defined as "hot tumor" and "cold tumor", having different levels of biological function, clinical prognosis, and immune cell infiltration. We obtained three gene clusters using the differentially expressed genes between the two cuproptosis-related subtypes, which were associated with different molecular activities and clinical characteristics. Next, we developed and validated a cuproptosis prognostic model that included two genes (FDX1 and DBT). The calculated risk score could divide patients into high- and low-risk groups. The high-risk group had a poorer prognosis, lower level of immune infiltration, higher frequency of gene alterations, and greater levels of FDX1 methylation and limited DBT methylation. The risk score was also an independent predictive factor for overall survival in KIRC. The established nomogram calculating the risk score achieved a high predictive ability for the prognosis of individual patients (area under the curve: 0.860). We then identified small molecular inhibitors as potential treatments and analyzed the sensitivity to chemotherapy of the signature genes. Tumor immune dysfunction and exclusion (TIDE) showed that the high-risk group had a higher level of TIDE, exclusion and dysfunction that was lower than the low-risk group, while the microsatellite instability of the high-risk group was significantly lower. The results of two independent immunotherapy datasets indicated that cuproptosis regulators could influence the response and efficacy of immunotherapy in KIRC. Our study provides new insights for individualized and comprehensive therapy of KIRC.

Development of an Independent Prognostic Signature Based on Three Hypoxia-Related Genes for Breast Cancer.

Background: Hypoxia was considered to be a prognostic indicator in a variety of solid tumors. This study aims at identifying the hypoxia-related genes (HRGs) in breast cancer (BC) and the feasibility of HRGs as a prognostic indicator. Methods: We downloaded the mRNA expression data of BC patients from TCGA and GEO databases. The LASSO Cox regression analysis was applied to screen the hub HRGs to establish a prognostic Risk Score. The independence of Risk Score was assessed by multivariate Cox regression analysis. And the immune checkpoint analysis was also performed. In addition, we also detected the expression level of hub HRGs in MCF-10A cells, MCF-7 cells, and SK-BR-3 cells by RT-qPCR. Results: Three HRGs were identified as hub genes with prognostic value in BC, including CA9, PGK1, and SDC1. The Risk Score constructed by these three genes could efficiently distinguish the prognosis of different BC patients and has been shown to be an independent prognostic indicator. In the high-risk group, patients had lower overall survival and poorer prognosis. In addition, the expression levels of five immune checkpoints (PD1, CTLA4, TIGIT, LAG3, and TIM3) in the high-risk group were significantly higher than those in the low-risk group. Moreover, the expression levels of PGK1 and SDC1 in BC cells were significantly increased. Conclusion: In this study, we established an efficiently model based on three optimal HRGs (CA9, PGK1, and SDC1) could clearly distinguish the prognosis of different BC patients.

Comprehensive analyses reveal the role of histone deacetylase genes in prognosis and immune response in low-grade glioma.

Many studies have shown that Histone deacetylases (HDAC) is involved in the occurrence of malignant tumors and regulates the occurrence, proliferation, invasion, and migration of malignant tumors through a variety of signaling pathways. In the present, we explored the role of Histone deacetylases genes in prognosis and immune response in low-grade glioma. Using consensus clustering, we built the new molecular clusters. Using HDAC genes, we constructed and validated the prognostic model in two independent cohort datasets. Patients were divided into high-risk and low-risk groups. Then, we explored the molecular characteristics, clinical characteristics, tumor microenvironment and immune infiltration levels of two clusters and risk groups. Receiver operating characteristic analyses were built for model assessment. We finally detected the expression levels of signature genes between tumor and normal tissues. Low-grade can be separated into two molecular clusters using 11 HDACs genes. Two clusters had different clinical characteristics and prognosis. Nex, we constructed a prognosis model using six HDAC genes (HDAC1, HDAC4, HDAC5, HDAC7, HDAC9, and HDAC10), which was also validated in an independent cohort dataset. Furthermore, multivariate cox regression indicated that the calculated risk score was independently associated with prognosis in low-grade glioma, and risk score can predict the five-year survival probability of low-grade glioma well. High-risk patients can be attributed to multiple complex function and molecular signaling pathways, and the genes alterations of high- and low-risk patients were significantly different. We also found that different survival outcomes of high- and low- risk patients could be involved in the differences of immune filtration level and tumor microenvironment. Subsequently, using signature genes, we identified several small molecular compounds that could be useful for low-grade glioma patients' treatment. Finally, we detected the expression levels of signature genes in tumor tissues. our study uncovers the biology function role of HDAC genes in low-grade glioma. We identified new molecular subtypes and established a prognostic model based on six HDAC genes, which was well applied in two independent cohort data. The regulation of HDAC genes in low-grade glioma involved in multiple molecular function and signaling pathways and immune infiltration levels. Further experiments in vivo and vitro were required to confirm the present findings.

Pan-cancer analysis of a novel indicator of necroptosis with its application in human cancer.

As a type of programmed cell death, necroptosis is thought to play a dual role in tumorigenesis. However, a comprehensive assessment of necroptosis-related regulators across human cancers has not been reported. Therefore, in this study, we established a quantitative index to evaluate the necroptosis rate and determine its correlations with clinical prognosis, signaling pathways and molecular features, immune cell infiltration and regulation, immunotherapy, and chemotherapy sensitivity across cancers. Our results indicated that the necroptosis score can act as a favorable or risky prognostic factor in various cancer types. A gene set variation analysis suggested that necroptosis is significantly associated with immune- and inflammation-related signaling pathways, cell growth and apoptosis, and energy metabolism. Furthermore, necroptosis can affect the tumor microenvironment and immunity regulation, and the effect of necroptosis on immunity is different in different tumor types. There is crosstalk between components of necroptosis, pyroptosis, ferroptosis and autophagy pathways in multiple types of cancers. Finally, the necroptosis rate can be an indicator of immunotherapy effectiveness in multiple cancers and can affect the chemotherapy sensitivity of cancer cells. Our study presents a characterization of necroptosis across human cancers, highlights the potential necroptotic effects on immune regulation, and provides new insights into the development of individualized tumor treatments and clinical applications of immunotherapy.

Molecular characterization, clinical relevance and immune feature of m7G regulator genes across 33 cancer types.

Over 170 RNA modifications have been identified after transcriptions, involving in regulation of RNA splicing, processing, translation and decay. Growing evidence has unmasked the crucial role of N6-methyladenosine (m6A) in cancer development and progression, while, as a relative newly found RNA modification, N7-methylguanosine (m7G) is also certified to participate in tumorigenesis via different catalytic machinery from that of m6A. However, system analysis on m7G RNA modification-related regulator genes is lack. In this study, we first investigated the genetic alteration of m7G related regulator genes in 33 cancers, and found mRNA expression levels of most regulator genes were positively correlated with copy number variation (CNV) and negatively correlated with methylation in most cancers. We built a m7G RNA modification model based on the enrichment of the regulator gene scores to evaluate the m7G modification levels in 33 cancers, and investigated the connections of m7G scores to clinical outcomes. Furthermore, we paid close attention to the role of m7G in immunology due to the widely used immune checkpoint blockade therapy. Our results showed the higher m7G scores related to immunosuppression of tumor cells. Further confirmation with phase 3 clinical data with application of anti-PDL1/PDL indicated the impact of m7G modification level on immunotherapy effect. Relevance of m7G regulator genes and drug sensitivity was also evaluated to provide a better treatment choice when treating cancers. In summary, our study uncovered the profile of m7G RNA modification through various cancers, and figured out the connection of m7G modification levels with therapeutical outcomes, providing potential better options of cancer treatment.

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis.

Background: Although immunotherapy has been widely used, there is currently no research comparing immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This meta-analysis addresses a gap in the comparison of immunotherapy efficacy, including immune checkpoint inhibitors (ICIs), chemotherapy (CT), radiotherapy (RT), and ICI combined CT or RT. Methods: A search of Pubmed, Cochrane, EMBASE, and ClinicalTrial.gov was conducted to identify studies which enrolled NSCLC patients with BM treated with ICIs. The outcomes consisted of intracerebral overall response rate (iORR), intracerebral disease control rate (iDCR), extracranial overall response rate (EORR), distant brain failure (DBF), local control (LC), progression-free survival (PFS), and overall survival (OS). Results: A total of 3160 participants from 46 trials were included in the final analysis. Patients treated with immunotherapy were associated with a longer PFS (0.48, 95%CI: 0.41-0.56), and a longer OS (0.64, 95%CI: 0.60-0.69) compared with immunotherapy-naive patients. In prospective studies, dual ICI combined CT and ICI combined CT achieved a better OS. The hazard ratio (HR) of dual ICI combined CT versus dual ICI was 0.61, and the HR of ICI combined CT versus ICI monotherapy was 0.58. Moreover, no statistical difference in PFS, OS, EORR, iORR, iDCR, and EDCR was found between patients with ICI monotherapy and ICI combined cranial radiotherapy. Concurrent ICI combined RT was shown to decrease the rate of DBF (OR = 0.15, 95% CI: 0.03-0.73) compared with RT after ICI. Patients treated with WBRT might have an inferior efficacy than those with SRS because the iORR of SRS was 0.75 (0.70, 0.80) and WBRT was 0. Furthermore, no obvious difference in PFS and OS was observed among the three different types of ICI, which targets PD-1, PD-L1, and CTLA-4, respectively. Conclusions: Patients treated with ICI got superior efficacy to those without ICI. Furthermore, dual ICI combined CT and ICI combined CT seemed to be optimal for NSCLC patients with BM. In terms of response and survival, concurrent administration of SRS and ICI led to better outcomes for patients with BMs than non-concurrent or non-SRS. Importance of the Study: In the new era of immunotherapy, our meta-analysis validated the importance of immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). By comparing the long-term and short-term impacts of various regimens, all immunotherapy treatments had superior efficacy to immunotherapy-naive. At the same time, through pairwise comparison in immunotherapy, our findings can help clinicians to make treatment decisions for NSCLC patients with BMs. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=269621, identifier CRD42021269621.

Identification of pyroptosis-related gene prognostic signature in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a life-threatening disease with poor prognosis. Pyroptosis has been recently disclosed as a programmed cell death triggered by invasive infection, involved in cancer development. However, the prognosis role of pyroptosis-related genes in HNSCC has not been discussed. METHODS: The RNA sequence data of pyroptosis-related genes were obtained from The Cancer Genome Atlas (TCGA) database. Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis were performed to screen the HNSCC survival-related signature genes. We established a HNSCC risk model with the identified prognostic genes, then divided the HNSCC patients into low- and high-risk subgroups according to median risk score. Moreover, we utilized Gene Expression Omnibus (GEO) dataset to validate the risk model. Go and KEGG analyses were conducted to reveal the potential function of differential expression of genes that identified between low- and high-risk subgroups. ESTIMATE algorithm was performed to investigate the immune infiltration of tumors. Correlation between signature gene expression and drug-sensitivity was disclosed by Spearman's analysis. RESULTS: We constructed a HNSCC risk model with identified seven pyroptosis-related genes (CASP1, GSDME, IL6, NLRP1, NLRP2, NLRP6, and NOD2) as prognostic signature genes. High-risk subgroup of HNSCC patients in TCGA cohort correlated with lower survival probability than patients from low-risk subgroup (p < .001), and the result is verified with GEO dataset. In addition, 161 genes were identified differentially expressed between the low- and high-risk subgroups in the TCGA cohort, mainly related to immune response. Higher PD-L1 expression level was found in the high-risk subgroup that indicated the possible employment of immune checkpoint inhibitors. IL6 was positively correlated with WZ3105 and MPS-1-IN-1 in the cancer therapeutics response portal database. CONCLUSION: We built and verified a risk model for HNSCC prognosis using seven pyroptosis-related signature genes, which could predict the overall survival of HNSCC patients and facilitate treatment.

Comprehensive analysis of histone deacetylases genes in the prognosis and immune infiltration of glioma patients.

The occurrence and development of tumors are closely related to histone deacetylases (HDACs). However, their relationship with the overall biology and prognosis of glioma is still unknown. In the present study, we developed and validated a prognostic model for glioma based on HDAC genes. Glioma patients can be divided into two subclasses based on eleven HDAC genes, and patients from the two subclasses had markedly different survival outcomes. Then, using six HDAC genes (HDAC1, HDAC3, HDAC4, HDAC5, HDAC7, and HDAC9), we established a prognostic model for glioma patients, and this prognostic model was validated in an independent cohort. Furthermore, the calculated risk score from six HDACA genes expression was found to be an independent prognostic factor that could predict the five-year overall survival of glioma patients well. High-risk patients have changes in multiple complex functions and molecular signaling pathways, and the gene alterations of high- and low-risk patients were significantly different. We also found that the different survival outcomes of high- and low-risk patients could be related to the differences in immune filtration levels and the tumor microenvironment. Subsequently, we identified several small molecular compounds that could be favorable for glioma patient treatment. Finally, the expression levels of HDAC genes from the prognostic model were validated in glioma and nontumor tissue samples. Our results revealed the clinical utility and potential molecular mechanisms of HDAC genes in glioma. A model based on six HDAC genes can predict the overall survival of glioma patients well, and these genes are potential therapeutic targets.

Silencing GOLGA8B inhibits cell invasion and metastasis by suppressing STAT3 signaling pathway in lung squamous cell carcinoma.

Changes to some Golgi subfamily member proteins are reported to be involved in tumor metastasis. However, the functional role and potential mechanism of the Golgi A8 family member B (GOLGA8B) in lung squamous cell carcinoma (LUSC) remains unknown. In the present study, GOLGA8B expression was detected using qRT-PCR, Western blot, and immunohistochemistry (IHC). In vivo animal experiments and in vitro functional assays were performed to explore the function of GOLGA8B in LUSC. Luciferase assays were performed to investigate the underlying targets of GOLGA8B in LUSC. GOLGA8B was shown to be highly expressed in LUSC metastasis tissue, and significantly associated with the distant metastasis-free survival of LUSC patients. Loss-of-function assays indicated that silencing GOLGA8B suppressed LUSC cell tumorigenesis in vivo and weakened in vitro invasion and migration. GOLGA8B silencing-induced inhibition of invasion and migration was associated with the inactivation of STAT3 signaling. Importantly, these results showed that the number of circulating tumor cells (CTCs) was markedly higher in the GOLGA8B silencing group than in the control vector group. GOLGA8B expression was positively associated with p-STAT3 expression in LUSC tissue. Study findings revealed a novel mechanism by which GOLGA8B promotes tumor metastasis in LUSC cells and suggests that this protein could be a promising target for antitumor metastasis therapy in LUSC patients.

Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients.

This study is aimed to establish a new glioma prognosis model by integrating the aging-related lncRNA expression profiles and clinical parameters of glioma patients enrolled in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas. The aging-related lncRNAs were explored using Pearson correlation analysis (|R|> 0.6, P < 0.001), and the prognostic signature in glioma patients was screened using univariate cox regression and least absolute shrinkage/selection operator regression. Based on the fifteen lncRNAs screened out, we divided the glioma patients into three subtypes, and developed a prognostic model. Kaplan-Meier survival curve analysis showed that low-risk patients survived longer time than high-risk patients. Principal component analysis indicated that the signature of aging-related lncRNAs was clearly distinct between the high- and low-risk groups. We also found the fifteen lncRNAs were closely correlated with 119 genes by establishing a co-expression network. Kyoto Encyclopedia of Genes and Genomes analysis displayed that the high- and low-risk groups were enriched in different functions and pathways. Different missense mutations were observed in the two groups, and the most frequent variant types were single nucleotide polymorphism. This study demonstrates that the novel aging-related lncRNAs signature has an important prognosis prediction ability and may contribute to individualized treatment for glioma.