miR-30c-5p inhibits esophageal squamous cell carcinoma progression by repressing the PI3K/AKT signaling pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors, with high incidence and poor prognosis. Revealing mechanisms of ESCC progression and developing new therapeutic targets remains crucial. The aim of this study was to elucidate the molecular mechanism of miR-30c-5p in regulating the malignant progression of ESCC. METHODS: TCGA, GEO, and other datasets were used to analyze the differential expression of miR-30c-5p in ESCC and adjacent tissues, and its impact on prognosis. Then the effects of miR-30c-5p on the proliferation, migration, and invasion of TE-1 and Eca9706 cells were investigated through proliferation experiments, transwell and wounding healing assays. The regulatory mechanism of miR-30c-5p on the PI3K/AKT signaling pathway and its interaction in cancer progression were investigated through Western blots, dual-luciferase reporter assay, and rescue experiments. RESULTS: miR-30c-5p was significantly downregulated in ESCC tissue and represented a poor prognosis. miR-30c-5p mimic significantly inhibited the proliferation, migration, and invasion ability of ESCC, while miR-30c-5p inhibitor significantly promoted tumor cell progression. Through bioinformatic analysis and experimental results, miR-30c-5p interacted directly with PIK3CA mRNA and inhibited subsequent signaling pathway activation. PIK3CA activator could eliminate the inhibitory effects of miR-30c-5p mimic on the progression of ESCC, while PIK3CA inhibitors could rescue the promoting effect of miR-30c-5p inhibitor group cells. CONCLUSIONS: In summary, we found that miR-30c-5p inhibited the proliferation, invasion and migration of ESCC by inhibiting PI3K/AKT signaling pathway for the first time, and this study is expected to provide a novel insight and potential therapeutic target for managing ESCC.

Unraveling the causality between gastroesophageal reflux disease and increased cancer risk: evidence from the UK Biobank and GWAS consortia.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. METHODS: This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. RESULTS: GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. CONCLUSIONS: This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.

The associations between dysregulation of human blood metabolites and lung cancer risk: evidence from genetic data.

BACKGROUND: Metabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear. METHODS: Genomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings. RESULTS: A total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer. CONCLUSION: This study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.

Neutrophils' dual role in cancer: from tumor progression to immunotherapeutic potential.

The tumor microenvironment (TME) is intricately associated with cancer progression, characterized by dynamic interactions among various cellular and molecular components that significantly impact the carcinogenic process. Notably, neutrophils play a crucial dual role in regulating this complex environment. These cells oscillate between promoting and inhibiting tumor activity, responding to a multitude of cytokines, chemokines, and tumor-derived factors. This response modulates immune reactions and affects the proliferation, metastasis, and angiogenesis of cancer cells. A significant aspect of their influence is their interaction with the endoplasmic reticulum (ER) stress responses in cancer cells, markedly altering tumor immunodynamics by modulating the phenotypic plasticity and functionality of neutrophils. Furthermore, neutrophil extracellular traps (NETs) exert a pivotal influence in the progression of malignancies by enhancing inflammation, metastasis, immune suppression, and thrombosis, thereby exacerbating the disease. In the realm of immunotherapy, checkpoint inhibitors targeting PD-L1/PD-1 and CTLA-4 among others have underscored the significant role of neutrophils in enhancing therapeutic responses. Recent research has highlighted the potential of using neutrophils for targeted drug delivery through nanoparticle systems, which precisely control drug release and significantly enhance antitumor efficacy. This review thoroughly examines the diverse functions of neutrophils in cancer treatment, emphasizing their potential in regulating immune therapy responses and as drug delivery carriers, offering innovative perspectives and profound implications for the development of targeted diagnostic and therapeutic strategies in oncology.

The genetic association between hyperthyroidism and heart failure: a Mendelian randomization study.

Background and aims: Hyperthyroidism is an endocrine disease with multiple etiologies and manifestations. Heart failure (HF) is a common, costly, and deadly medical condition in clinical practice. Numerous studies have suggested that abnormal thyroid function can induce or aggravate the development of heart disease. However, no study has demonstrated a causal relationship between hyperthyroidism and heart failure. Therefore, the purpose of this study was to explore the causal link between hyperthyroidism and HF. Methods: Summary data for genetically predicted hyperthyroidism were obtained from a genetic association study. The data examined for genetically determined all-cause heart failure came from 218,208 individuals from the FinnGen Consortium. Two-sample Mendelian randomization (MR) analysis was used to estimate the causal link between hyperthyroidism and heart failure. Statistical analyses were conducted using the inverse variance-weighted, weighted median, simple median, weighted mode, MR-PRESSO (number of distribution = 5000), MR-Egger, and leave-one-out. Results: The results of the inverse-variance weighted analysis indicated a causal association between hyperthyroidism and an increased risk of all-cause heart failure (IVW: ß=0.048, OR=1.049, 95%CI: [1.013 to 1.087], P=0.007). Similarly, the weighted median approach demonstrated a positive correlation between hyperthyroidism and all-cause heart failure (OR=1.049, [95% CI, 1.001-1.100]; P=0.044). Additionally, no horizontal pleiotropy or heterogeneity was observed. The leave-one-out analysis revealed that the majority of the SNP-driven associations were not influenced by a single genetic marker. Conclusion: Our study observed a causal relationship between hyperthyroidism and all-cause heart failure. Hyperthyroidism may associate with heart failure genetically.

CDK16 as a potential prognostic biomarker correlated with an immunosuppressive tumor microenvironment and benefits in enhancing the effectiveness of immunotherapy in human cancers.

BACKGROUND: Cyclin-Dependent Kinase 16 (CDK16) plays significant biological roles in various diseases. Nonetheless, its function in different cancer types and its relationship with the Tumor Immune Microenvironment (TIME) are still not well-understood. METHODS: We analyzed the expression profile, genetic alterations, clinical features, and prognostic value of CDK16 in pan-cancer using data from The Cancer Genome Atlas, Genotype-Tissue Expression databases, and in vitro experiments. Additionally, the TIMER2 and ImmuCellAI databases were utilized to assess the correlation between CDK16 expression and immune cell infiltration levels. Finally, we examined the correlation between CDK16 and the response to immunotherapy using collected immunotherapy data. RESULTS: CDK16 is notably overexpressed in pan-cancer and is a risk factor for poor prognosis in various cancers. Our findings reveal that CDK16 regulates not only cell cycle-related functions to promote cell proliferation but also the autoimmunity-related functions of the innate and adaptive immune systems, along with other immune-related signaling pathways. Moreover, CDK16 overexpression contributes to an immunosuppressive tumor microenvironment, extensively suppressing immune-related features such as the expression of immune-related genes and pathways, as well as the count of immune-infiltrating cells. Our analysis indicated that individuals with low CDK16 expression showed higher response rates to immune checkpoint inhibitors and longer overall survival compared to those with high CDK16 expression. CONCLUSIONS: This study establishes CDK16 as a potential biomarker for predicting poor prognosis in a wide range of cancers. Its role in shaping the immunosuppressive tumor microenvironment and influencing the efficacy of immunotherapy highlights the urgent need for developing targeted therapies against CDK16, offering new avenues for cancer treatment and management.

Establishment of Ferroptosis-Associated Molecular Subtypes and Hub Genes Related to the Immune Microenvironment of Heart Failure.

BACKGROUND: Ferroptosis is a form of iron-dependent regulated cell death, and prior work has highlighted the potential utility of ferroptosis-inducing agents as tools to treat heart failure (HF). To date, however, no detailed examinations of the prognostic utility of ferroptosis-related genes (FRGs) in HF have been conducted. METHODS: We used established genomic identification of FRGs for total samples in the gene expression omnibus (GEO) database, screened for differentially expressed FRGs, performed protein-protein interaction analysis and functional analysis of HF immune microenvironment subtypes. Subsequently, we applied tools to calculate immune cell infiltration, compare immune cell, immune response genomic and HLA gene differences between subtypes, and perform candidate drug identification. Finally, preliminary in vivo validation of the screened central genes was performed in animal models. RESULTS: FRGs were compared between samples from HF and healthy control donors, revealing 62 of these genes to be differentially expressed as a function of HF status. HF patient-derived tissues exhibited significant changes in the expression of HLA genes, increase immune cell infiltration, and higher levels of other immune-related genes within the associated immune microenvironment. These FRGs were then leveraged to establish two different immune-related subtypes of HF based on clustering analysis results, after which these subtypes were characterized in further detail. Functional enrichment analyses revealed the identified differentially expressed genes to be enriched in key immune-related pathways including the primary immunodeficiency, natural killer cell-mediated cytotoxicity, FcϵRI signaling, and antigen processing and presentation pathways. The impact of the immune microenvironment was also explored through functional analyses, core gene analyses, and efforts to identify potential drug candidates for HF patients. Moreover, four key hub genes were identified as promising targets for therapeutic intervention in HF, including HDAC1, LNPEP, PSMA1, and PSMA6. Subsequent preclinical work in a mouse model system supported a potential role for HDAC1 as an important biomarker associated with the incidence of HF. CONCLUSIONS: To sum up, these results emphasize the importance of ferroptosis as a regulator of the HF-related immune microenvironment, highlighting viable avenues for the further study of molecular targets amenable to pharmacological intervention with the aim of treating this debilitating disease.

HGH1 and the immune landscape: a novel prognostic marker for immune-desert tumor microenvironment identification and immunotherapy outcome prediction in human cancers.

HGH1 homolog, a protein-coding gene, plays a crucial role in human growth and development. However, its role in human cancer remains unclear. For the first time, this study comprehensively evaluated the potential involvement of HGH1 in cancer prognosis and immunological function. To achieve this, data from various databases, including The Cancer Genome Atlas, Genotype Tissue Expression, Cancer Cell Lineage Encyclopedia, Human Protein Atlas, cBioPortal, Tumor Immune Estimation Resource and Immune Cell Abundance Identifier, were collated, as well as from one large clinical study, three immunotherapy cohorts and in vitro experiments. This study aims to elucidate the role of HGH1 expression in cancer prognosis and immune response. Our findings revealed a significant association between increased HGH1 expression and a worse prognosis across various cancer types. Predominantly, copy number variations were identified as the most common genetic mutations. Additionally, HGH1 was observed to not only regulate cell cycle-related functions to promote cell proliferation but also influence autoimmunity-related functions within both the innate and adaptive immune systems, along with other relevant immune-related signaling pathways. Gene set enrichment analysis and gene set variation analysis were used to substantiate these findings. HGH1 overexpression contributed to an immune-deficient (immune-desert) tumor microenvironment, which was characterized by a significant expression of immune-related features such as immune-related gene and pathway expression and the number of immune-infiltrating cells. Furthermore, the correlation between HGH1 expression and tumor mutational burden in four cancers and microsatellite instability in eight cancers was observed. This suggests that HGH1 has potential as an immunotherapeutic target. Immunotherapy data analysis supports this notion, demonstrating that patients with low HGH1 expression treated with immune checkpoint inhibitors exhibit improved survival rates and a higher likelihood of responding to immunotherapy than patients with high HGH1 expression. Collectively, these findings highlight the significant role of HGH1 in human cancers, illuminating its involvement in tumorigenesis and cancer immunity. Elevated HGH1 expression was identified to be indicative of an immune-desert tumor microenvironment. Consequently, the targeting of HGH1, particularly in combination with immune checkpoint inhibitor therapy, holds promise for enhancing therapeutic outcomes in patients with cancer.

Unraveling the molecular crosstalk and immune landscape between COVID-19 infections and ischemic heart failure comorbidity: New insights into diagnostic biomarkers and therapeutic approaches.

BACKGROUND: Coronavirus disease 2019 (COVID-19), resulting from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), remains a persistent global health concern. Evidence has highlighted a significant association between COVID-19 and ischemic heart failure (IHF), contributing to disease progression and increased mortality. This study identified diagnostic biomarkers for these comorbidities and elucidated disease progression's molecular mechanisms. METHODS: We retrieved differentially expressed gene (DEG) data for COVID-19 and IHF from publicly available microarray and RNA-Seq datasets to investigate the underlying mechanisms and potential pathways associated with the co-occurrence of COVID-19 and IHF. By intersecting the results from the two diseases, we obtained diagnostic biomarkers using SVM-RFE and LASSO algorithms. Animal experiments and immunological analyses were conducted to help understand the association between SARS-CoV-2 and IHF in patients, enabling early diagnosis of disease progression. Finally, we analyzed the regulatory network of critical genes and identified potential drug compounds that could target the genetic links identified in our study. RESULTS: 1974 common DEGs were identified between COVID-19 and IHF, contributing to disease progression and potential cancer risk by participating in immune and cancer-related pathways. In addition, we identified six hub genes (VDAC3, EIF2AK2, CHMP5, FTL, VPS4A, and CHMP4B) associated with the co-morbidity, and their diagnostic potential was confirmed through validation using relevant datasets and a mouse model. Functional enrichment analysis and examination of immune cell infiltration revealed immune dysregulation after disease progression. The comorbid hub genes exhibited outstanding immunomodulatory capacities. We also constructed regulatory networks tightly linked to both disorders, including transcription factors (TFs), miRNAs, and genes at both transcriptional and post-transcriptional levels. Finally, we identified 92 potential drug candidates to enhance the precision of anti-comorbidity treatment strategies. CONCLUSION: Our study reveals a shared pathogenesis between COVID-19 and IHF, demonstrating that their coexistence exacerbates disease severity. By identifying and consolidating hub genes as pivotal diagnostic biomarkers for COVID-19 and IHF comorbidity, we have made significant advancements in understanding the underlying mechanisms of these conditions. Moreover, our study highlights dysregulated immunity and increased cancer risk in the advanced stages of disease progression. These findings offer novel perspectives for diagnosing and treating IHF progression during SARS-CoV-2 infection.

UBE2V2 promotes metastasis by regulating EMT and predicts a poor prognosis in lung adenocarcinoma.

PURPOSE: As a member of the ubiquitin-conjugating enzyme (E2) family, UBE2V2 demonstrates significant tumorigenicity in many cancers. However, the relationship between UBE2V2 expression and the morbidity of lung adenocarcinoma (LUAD) is still unknown. METHODS: We detected the mRNA and protein expression of UBE2V2 and analyzed its relationship with clinical parameters as well as survival prognosis based on bioinformatic and immunohistochemistry (IHC) in LUAD. The signaling pathway of UBE2V2 in the development of LUAD was obtained by GSEA. The TIMER database was used to investigate the association between UBE2V2 expression and the level of infiltration of different immune cells. Finally, we explored the effects of UBE2V2 knockdown on the proliferation, apoptosis, and migration of LUAD cells. RESULTS: The results showed that UBE2V2 was a potential oncogene and might be considered an independent prognostic molecule for LUAD patients based on TCGA prediction (HR: 1.497 p = 0.012) and IHC (HR:1.864 p = 0.044). IHC showed that UBE2V2 was related to the following clinicopathological factors: gender (p = 0.043), stage (p = 0.042), and lymph node metastasis (p = 0.002). Finally, knockdown of UBE2V2 reduced the migration of LUAD cells by regulating EMT-related proteins. Knockdown of UBE2V2 induced LUAD cells to arrest in the G1 phase. Knockdown of UBE2V2 increased LUAD cell apoptosis and decreased proliferation, which might be related to the downregulation of PCNA and upregulation of P53 and ƳH2AX expression. Interestingly, UBE2V2 is negatively correlated with B cells, CD4+ T cells, macrophages, and dendritic cells. CONCLUSION: UBE2V2 may be a valuable therapeutic target for lung cancer.

Signal sequence receptor subunit 3: A novel indicator of immunosuppressive tumor microenvironment and clinical benefits from immunotherapy.

BACKGROUND: Signal sequence receptor subunit 3 (SSR3), a translocation-associated protein complex, plays a vital role in various diseases. However, its involvement in human cancers remains unclear. METHODS: We conducted a comprehensive analysis by integrating data from multiple sources, including the Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia, Genotype Tissue Expression, Human Protein Atlas, cBioPortal, TIMER, and ImmuCellAI. Additionally, we incorporated data from a clinical trial, two immunotherapy cohorts, and in vitro experiments to investigate SSR3's impact on cancer prognosis and immune response. RESULTS: Our findings revealed a significant correlation between elevated SSR3 expression and unfavorable prognosis across various cancer types. Amplification is the most common genetic alteration in SSR3. Furthermore, functional enrichment analysis highlighted SSR3's regulatory role in promoting proliferation. In addition, SSR3 also serves as a pivotal mediator bridging the innate and adaptive immune systems and several related signaling pathways. Moreover, the correlation of SSR3 expression with tumor mutation burden in five cancer types, as well as with microsatellite instability in nine cancer types, suggests the potential of SSR3 as a predictive marker for immunotherapy response. To validate this hypothesis, we examined data from patients who underwent immunotherapy treatment. Our analysis revealed that individuals with low SSR3 expression demonstrated higher response rates to immune checkpoint inhibitors and longer overall survival compared to those with high SSR3 expression. CONCLUSIONS: Our study identifies SSR3 as a potential oncogene in humans, implicated in both tumorigenesis and cancer immunity. Elevated SSR3 expression is indicative of an immunosuppressive tumor microenvironment. Therefore, SSR3 holds promise as a potential prognostic biomarker and a target for immunotherapy in cancer treatment.

The circadian rhythm key gene ARNTL2: a novel prognostic biomarker for immunosuppressive tumor microenvironment identification and immunotherapy outcome prediction in human cancers.

Background: Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) belongs to the b HLH- PAS domain transcription factor family and is one of the key clock genes that control the circadian rhythm. ARNTL2 plays an important role in human biological functions. However, its role in various tumors, especially in the tumor immune microenvironment (TIME) and immunotherapy, remains unclear. Methods: We integrated data from cancer patients from multiple databases, including the Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia, Genotype Tissue Expression, Human Protein Atlas, cBioPortal, TIMER, and ImmuCellAI, with data from a large clinical study, three immunotherapy cohorts, and in vitro experiments to investigate the involvement of ARNTL2 expression in cancer prognosis and immune response. Results: ARNTL2 displayed abnormal expression within most malignant tumors, and is significantly associated with poorer survival and pathologic staging. Through gene-set enrichment analysis (GSEA) and gene-set variation analysis (GSVA), we found that ARNTL2 not only regulates cell cycle-related functions to promote cell proliferation but also regulates autoimmunity-related functions of the innate and adaptive immune systems, and other immune-related signaling pathways. In addition, ARNTL2 overexpression contributes to an immunosuppressive tumor microenvironment that plays a key role in immunosuppression-related features, such as the expression of immunosuppression-related genes and pathways and the number of immunosuppressive-infiltrating cells, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). The group of patients with low ARNTL2 expression who received immune checkpoint inhibitors (ICI) therapy had better response rates and longer survival when compared to those with high ARNTL2 expression. Conclusion: The findings of this study suggest that ARNTL2 is a potential human oncogene that plays an important role in tumorigenesis and cancer immunity. Elevated ARNTL2 expression indicates an immunosuppressive tumor microenvironment. Targeting ARNTL2 in combination with ICI therapy could bring more significant therapeutic benefits to patients with cancer. Our study sheds light on the remarkable potential of ARNTL2 in tumor immunity and provides a novel perspective for anti-tumor strategies.

Shedding light on macrophage immunotherapy in lung cancer.

The search for therapeutic options for lung cancer continues to advance, with rapid advances in the search for therapies to improve patient prognosis. At present, systemic chemotherapy, immune checkpoint inhibitor therapy, antiangiogenic therapy, and targeted therapy for driver gene positivity are available in the clinic. Common clinical treatments fail to achieve desired outcomes due to immunosuppression of the tumor microenvironment (TME). Tumor immune evasion is mediated by cytokines, chemokines, immune cells, and other cells such as vascular endothelial cells within the tumor immune microenvironment. Tumor-associated macrophages (TAMs) are important immune cells in the TME, inducing tumor angiogenesis, encouraging tumor cell proliferation and migration, and suppressing antitumor immune responses. Thus, TAM targeting becomes the key to lung cancer immunotherapy. This review focuses on macrophage phenotype, polarization mechanism, role in lung cancer, and advances in macrophage centric immunotherapies.

Cuproptosis-related signature predicts prognosis, immunotherapy efficacy, and chemotherapy sensitivity in lung adenocarcinoma.

Background: Cuproptosis is a novel form of programmed cell death that disrupts the tricarboxylic acid (TCA) cycle and mitochondrial function. The mechanism of cuproptosis is quite different from that of common forms of cell death such as apoptosis, pyroptosis, necroptosis, and ferroptosis. However, the potential connection between cuproptosis and tumor immunity, especially in lung adenocarcinoma (LUAD), is poorly understood. Methods: We used machine learning algorithms to develop a cuproptosis-related scoring system. The immunological features of the scoring system were investigated by exploring its association with clinical outcomes, immune checkpoint expression, and prospective immunotherapy response in LUAD patients. The system predicted the sensitivity to chemotherapeutic agents. Unsupervised consensus clustering was performed to precisely identify the different cuproptosis-based molecular subtypes and to explore the underlying tumor immunity. Results: We determined the aberrant expression and prognostic relevance of cuproptosis-related genes (CRGs) in LUAD. There were significant differences in survival, biological function, and immune infiltration among the cuproptosis subtypes. In addition, the constructed cuproptosis scoring system could predict clinical outcomes, tumor microenvironment, and efficacy of targeted drugs and immunotherapy in patients with LUAD. After validating with large-scale data, we propose that combining the cuproptosis score and immune checkpoint blockade (ICB) therapy can significantly enhance the efficacy of immunotherapy and guide targeted drug application in patients with LUAD. Conclusion: The Cuproptosis score is a promising biomarker with high accuracy and specificity for determining LUAD prognosis, molecular subtypes, immune cell infiltration, and treatment options for immunotherapy and targeted therapies for patients with LUAD. It provides novel insights to guide personalized treatment strategies for patients with LUAD.

Cutting edges and therapeutic opportunities on tumor-associated macrophages in lung cancer.

Lung cancer is a disease with remarkable heterogeneity. A deep understanding of the tumor microenvironment (TME) offers potential therapeutic strategies against this malignant disease. More and more attention has been paid to the roles of macrophages in the TME. This article briefly summarizes the origin of macrophages, the mutual regulation between anti-tumoral immunity and pro-tumoral statuses derived from macrophage polarization, and the therapeutic opportunities targeting alternately activated macrophages (AAM)-type macrophage polarization. Among them, cellular components including T cells, as well as acellular components represented by IL-4 and IL-13 are key regulators driving the polarization of AAM macrophages. Novel treatments targeting macrophage-associated mechanisms are mainly divided into small molecule inhibitors, monoclonal antibodies, and other therapies to re-acclimate AMM macrophages. Finally, we paid special attention to an immunosuppressive subgroup of macrophages with T cell immunoglobulin and mucin domain-3 (TIM-3) expression. Based on cellular interactions with cancer cells, TIM3+ macrophages facilitate the proliferation and progression of cancer cells, yet this process exposes targets blocking the ligand-receptor recognition. To sum up, this is a systematic review on the mechanism of tumor-associated macrophages (TAM) polarization, therapeutic strategies and the biological functions of Tim-3 positive macrophages that aims to provide new insights into the pathogenesis and treatment of lung cancer.

Identification of nanoparticle-mediated siRNA-ASPN as a key gene target in the treatment of keloids.

Background: Keloid, also known as connective tissue hyperplasia, is a benign proliferative disorder with a global distribution. The available therapeutic interventions are steroid injections, surgical removal of keloids, radiotherapy, compression therapy, the application of cryosurgery, and many other methods. Objectives: Existing treatments or approaches for keloids may lead to similar or even larger lesions at the site of keloid excision, leading to a high recurrence rate. Therefore, this study aims at identifying a new gene-based therapy for the treatment of keloids. Methods: An ASPN-siRNA/nanoparticle combination (si-ASPN) and a negative siRNA/nanoparticle complex (NC) was developed on the basis of bioinformatics studies and used in vitro and in vivo experiments. Results: The results showed a strong correlation between the development of keloids and high expression of ASPN protein. With the expression of ASPN protein greatly reduced in keloid fibroblasts and nude mice allografts after treatment with si-ASPN, the collagen and fibroblasts were also uniform, thinner, parallel and regular. Conclusion: All the above experimental results suggest that keloid and ASPN are closely related and both fibroblast growth and metabolism of keloid are inhibited after silencing ASPN. Therefore, ASPN-siRNA delivered via nanoparticles can serve as a novel intervention therapy for the treatment of keloids.

Development and validation of a TRP-related gene signature for overall survival prediction in lung adenocarcinoma.

The transient receptor potential (TRP) channel is a type of channel protein widely distributed in peripheral and central nervous systems. Genes encoding TRP can be regulated by natural aromatic substances and serve as a therapeutic target for many diseases. However, the role of TRP-related genes in lung adenocarcinoma (LUAD) remains unclear. In this study, we used data from TCGA to screen and identify 17 TRP-related genes that are differentially expressed between LUAD and normal lung tissues. Based on these differentially expressed genes (DEGs), we classified all patients with LUAD into two subtypes. Significant differences in prognosis, clinical features, and immune cell infiltration characteristics were observed between the two subtypes. Subsequently, a prognostic signature with 12 genes was established by applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, and all patients with LUAD were classified into low- and high-risk groups. Patients with LUAD in the low-risk group had a significantly longer survival time than those in the high-risk group (p < 0.001), which was confirmed by LUAD data from the GSE72094 and GSE68571 validation datasets. Combined with clinical characteristics, the risk score was found to be an independent predictor of overall survival (OS) in patients with LUAD. Additionally, patients with high TRP scores exhibited poorer clinical characteristics and immune status while showing a sensitive response to chemotherapeutic agents. In conclusion, the TRP score is a promising biomarker for determining the prognosis, molecular subtype, tumor microenvironment, and guiding personalized treatment in patients with LUAD.

Pyrroloquinoline quinone modulates YAP-related anti-ferroptotic activity to protect against myocardial hypertrophy.

Background: Pyrroloquinoline quinone (PQQ) has been reported to exhibit cardioprotective and antioxidant activities. Accordingly, this study was developed to explore the effects of PQQ treatment on myocardial hypertrophy and the underlying mechanism of action governing any observed beneficial effects. Methods: A transverse aortic constriction (TAC) model of myocardial hypertrophy was established in vivo using C57BL/6 mice, while neonatal murine cardiomyocytes were stimulated with phenylephrine (PE) as an in vitro validation model system. Results: Treatment of TAC model mice with PQQ significantly suppressed myocardial hypertrophy and fibrosis, in addition to inhibiting the ferroptotic death of hypertrophic myocardial cells in vivo. Subsequent in vitro analyses revealed that treatment with PQQ was sufficient to significantly alleviate PE-induced hypertrophic activity and to prevent ferroptotic induction in these primary murine cardiomyocytes. At the mechanistic level, PQQ was found to promote the upregulation of Yes-associated Protein (YAP), to suppress YAP phosphorylation, and to drive the nuclear translocation of YAP within hypertrophic cardiomyocytes. The use of a specific siRNA construct to knock down YAP expression in vitro further confirmed the ability of PQQ to protect against myocardial hypertrophy at least in part through anti-ferroptotic mechanisms. Conclusion: PQQ can regulate the pathogenesis of myocardial hypertrophy through the induction of YAP-related anti-ferroptotic activity, highlighting the potential value of PQQ as a novel therapeutic agent capable of slowing or preventing the progression of myocardial hypertrophy and thus delaying the onset of heart failure.

AP3S1 is a Novel Prognostic Biomarker and Correlated With an Immunosuppressive Tumor Microenvironment in Pan-Cancer.

Background: Adaptor-related protein complex 3, sigma one subunit (AP3S1) is one of the encoding subunits of the adaptor complex AP-3. However, its role in various tumor types and relationship with the tumor immune microenvironment (TIME) remains unclear. Methods: AP3S1 expression was analyzed using datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, UALCAN, and HPA databases. Then, we performed a systematic analysis of the genetic alterations, clinical features, and prognostic value of AP3S1 in pan-cancer. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to identify the signaling pathways associated with AP3S1. The correlation between immune cell infiltration and AP3S1 expression was analyzed using immune cell infiltration data from the ImmuCellAI, TIMER2, and a previous study. Finally, we analyzed the association of AP3S1 with tumor mutational burden (TMB), microsatellite instability (MSI), and immune-related genes. Results: We found AP3S1 overexpression in most tumors and a significant association with low survival rates. GSEA and GSVA results show that AP3S1 is involved in tumor progression and associated with immune pathways in different tumor types. We also found that AP3S1 expression was positively correlated with the level of infiltration of immunosuppressive cells (tumor-associated macrophages, cancer-associated fibroblasts, Tregs) and negatively correlated with immune killer cells, including NK cells and CD8+ T cells, in pan-cancer. The expression of AP3S1 could affect TMB and MSI in various cancers. In addition, AP3S1 was positively correlated with most immunosuppressive genes, including PD-1, PD-L1, CTLA4, LAG3 and TIGIT in most cancer types. Conclusion: Our study reveals that AP3S1 is a potential pan-cancer oncogene and plays an essential role in tumorigenesis and cancer immunity. Elevated expression of AP3S1 indicates an immunosuppressive microenvironment and can be used as a potential prognostic biomarker and a target for immunotherapy.

Single-Cell Sequencing Analysis and Multiple Machine Learning Methods Identified G0S2 and HPSE as Novel Biomarkers for Abdominal Aortic Aneurysm.

Identifying biomarkers for abdominal aortic aneurysms (AAA) is key to understanding their pathogenesis, developing novel targeted therapeutics, and possibly improving patients outcomes and risk of rupture. Here, we identified AAA biomarkers from public databases using single-cell RNA-sequencing, weighted co-expression network (WGCNA), and differential expression analyses. Additionally, we used the multiple machine learning methods to identify biomarkers that differentiated large AAA from small AAA. Biomarkers were validated using GEO datasets. CIBERSORT was used to assess immune cell infiltration into AAA tissues and investigate the relationship between biomarkers and infiltrating immune cells. Therefore, 288 differentially expressed genes (DEGs) were screened for AAA and normal samples. The identified DEGs were mostly related to inflammatory responses, lipids, and atherosclerosis. For the large and small AAA samples, 17 DEGs, mostly related to necroptosis, were screened. As biomarkers for AAA, G0/G1 switch 2 (G0S2) (Area under the curve [AUC] = 0.861, 0.875, and 0.911, in GSE57691, GSE47472, and GSE7284, respectively) and for large AAA, heparinase (HPSE) (AUC = 0.669 and 0.754, in GSE57691 and GSE98278, respectively) were identified and further verified by qRT-PCR. Immune cell infiltration analysis revealed that the AAA process may be mediated by T follicular helper (Tfh) cells and the large AAA process may also be mediated by Tfh cells, M1, and M2 macrophages. Additionally, G0S2 expression was associated with neutrophils, activated and resting mast cells, M0 and M1 macrophages, regulatory T cells (Tregs), resting dendritic cells, and resting CD4 memory T cells. Moreover, HPSE expression was associated with M0 and M1 macrophages, activated and resting mast cells, Tregs, and resting CD4 memory T cells. Additional, G0S2 may be an effective diagnostic biomarker for AAA, whereas HPSE may be used to confer risk of rupture in large AAAs. Immune cells play a role in the onset and progression of AAA, which may improve its diagnosis and treatment.