High Aggressiveness Research Articles

Pesticide exposure and oxidative stress generation are linked to poor prognosis outcomes in breast cancer women carrying the allelic variant rs7438135 in the UGT2B7 gene.

Pesticide exposure is a risk factor for the development of several diseases, including breast cancer (BC). The enzyme UGT2B7 participate in detoxification of pesticides and the presence rs7438135 (G > A) variant in your gene increases its glucuronidation potential, contributing to oxidative stress metabolites neutralization. Here we investigated the impact of occupational pesticide exposure on the systemic oxidative stress generation from 228 women with BC depending on their UGT2B7 rs7438135 (G > A) status. q-PCR investigated the presence of the rs7438135 variant, and oxidative stress markers (lipid peroxidation levels, total antioxidant capacity-TRAP, and nitric oxide metabolites-NOx) were measured in plasma. Pesticide exposure induced significant augment in the systemic lipid peroxidation in the presence of the variant for several clinicopathological conditions, including tumors with high proliferation index (ki67) and with high aggressiveness. NOx was augmented in high ki67, positive progesterone receptors, high-grade and triple-negative/Luminal B tumors, and low-risk stratified patients. TRAP was depleted in young patients at menopause and those with triple-negative/Luminal B tumors, as well as those stratified as at low risk for death and recurrence. These findings showed that the presence of the variant was not able to protect from pesticide-induced oxidative stress generation in BC patients.

A basement membrane-related signature for prognosis and immunotherapy benefit in bladder cancer based on machine learning

BackgroundBladder cancer has a poor clinical outcome because of its high aggressiveness. Basement membrane plays vital functions in tumor invasion and migration. Invasion and distant metastasis of cancer are facilitated by degradation of the basement membrane and extracellular matrix.MethodsTen machine learning methods were utilized to develop the basement membrane-related signature (MRS) using datasets from TCGA, GSE13507, GSE31684, GSE32984 and GSE48276. Three anti-PD1 or anti-CTLA4 datasets and several predicting scores were used to investigate the performance of MRS in predicting the immunotherapy benefits.ResultsA predicting model based on the Enet algorithm (alpha = 0.1) was chosen as the optimal MRS since it had the highest average C-index being 0.72. According to TCGA data, the MRS showed good performance in predicting bladder cancer patients' clinical outcomes, with area under curves of 0.744, 0.766 and 0.817 for 1, 3, and 5-year receiver operating characteristic curve, respectively. PD1 and CTLA4 immunophenoscopes were associated with a low MRS score, as well as a lower tumor immune dysfunction and exclusion score. As MRS score increased, immune-activated cells levels decreased, tumor immune dysfunction and exclusion score decreased, immune escape score decreased, intratumor heterogeneity score decreased, PD1&CTLA4 immunophenoscore increased, and tumor mutational burden score increased in bladder cancer, suggesting better immunotherapy benefits. Bladder cancer cases with high MRS score was correlated with higher cancer related hallmark scores, including NOTCH and glycolysis signaling.ConclusionA new MRS has been developed for bladder cancer, which could be used to predict prognosis and the success of immunotherapy.

Novel Predictive Biomarkers in the Head and Neck Squamous Cell Carcinoma (HNSCC).

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, characterized by high aggressiveness and frequent metastasis to regional lymph nodes. Despite advances in therapy, including checkpoint inhibitor immunotherapy, surgery, radiotherapy, and chemotherapy, survival rates for patients with advanced HNSCC remain unsatisfactory. This article presents the latest research on predictive biomarkers such as PD-L1, PD-1, CTLA-4, p53, and HPV, which may enhance treatment efficacy and improve clinical outcomes for patients. The clinical value of these biomarkers, their limitations, and their potential application in HNSCC therapy are emphasized. Special attention is given to immunotherapy, which shows promising results in treating this type of cancer through the modulation of the immune response. The review's findings highlight the need for further research on new biomarkers to develop more personalized and effective therapeutic strategies for HNSCC patients.

Melatonin increases Olaparib sensitivity and suppresses cancer-associated fibroblast infiltration via suppressing the LAMB3-CXCL2 axis in TNBC

Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype, characterized with high aggressiveness and a high recurrence rate. Olaparib is the first US Food and Drug Administration-approved poly(ADP ribose) polymerase (PARP) inhibitor (PARPi) to treat breast cancer patients with a germline BRCA1 or BRCA2 mutation. However, resistance to Olaparib treatment restricts the therapeutic effects, and thus novel therapeutics are urgently required. In the present study, we identified that the combination of melatonin and Olaparib synergistically enhanced the sensitivity of TNBC cells. Moreover, melatonin exerted promising antitumor activities in Olaparib-resistant cells, implying the potential for its clinical application. An RNA-sequencing analysis revealed that melatonin treatment downregulated laminin subunit beta 3 (LAMB3) expression. Genetic ablation of LAMB3 significantly increased Olaparib sensitivity, and subsequently suppressed proliferation, epithelial-to-mesenchymal transition (EMT)-related gene expressions, and aggressiveness of breast cancer cells. Accordingly, LAMB3 expression was positively correlated with C-X-C motif chemokine ligand 2 (CXCL2), and they collaboratively promoted cancer-associated fibroblast (CAF) infiltration. An in vivo study demonstrated that combined treatment with melatonin and Olaparib showed enhanced inhibitory efficacy against tumor growth, LAMB3 expression, CXCL2 levels, and CAF infiltration compared to single treatment groups, and combined treatment with melatonin and Olaparib significantly ameliorated the immunosuppressive tumor microenvironment. These findings illustrate a promising therapeutic strategy using melatonin to overcome Olaparib resistance and activate antitumor immunity via attenuating the LAMB3-CXCL2 axis in breast cancer patients.

The influence of vehicle size on perception and behavior toward drivers

ABSTRACT This study examines the effects of vehicle size on driver impressions and behavioral intentions. Study 1 tested whether vehicle size (large vs. small) affects perceived physical size (height, body shape) through socioeconomic status (SES). We found that large (vs. small) vehicle drivers were perceived as tall (vs. short), and this perception was mediated by the drivers’ estimated SES (but not by body shape). Study 2 focused on aggressive behavioral intentions (e.g. honking) toward other drivers, examining whether the relationship between vehicle size and intention was serially mediated by estimated physical size and traits (aggression, power). Here, large (vs. small) vehicle driver were perceived as tall (heavy) and possessing high power (high aggression), which is related to less (more) aggressive behavioral intention toward the driver. Our study suggests that individuals perceive other drivers’ physical sizes differently, and this perception is associated with differences in behavioral responses toward other drivers.

Elucidating the molecular markers and biological pathways associated with extrahepatic cholangiocarcinoma: a transcriptome sequencing study.

Cholangiocarcinoma is a malignancy with high aggressiveness, and extrahepatic cholangiocarcinoma (ECCA) represents the predominant subtype. However, the molecular architecture and underlying pathogenic mechanisms of ECCA remain poorly understood. The objective of this study is to elucidate the molecular markers and biological pathways associated with ECCA. In order to identify the factors influencing ECCA, we conducted transcriptome sequencing on a cohort of 8 surgically resected ECCA specimens. To validate our findings, we integrated data from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases using batch integration analysis. Finally, we confirmed our results using clinical samples. The findings of this study reveal that through the analysis of sequencing data, we have successfully identified the genes that are differentially expressed and have a significant role in the development of ECCA. Utilizing the Weighted Gene Co-expression Network Analysis approach, we have integrated these identified gene modules with the GEO dataset, leading to the identification of four key genes (PTGDS, ITIH2, LSAMP, HBB) that are strongly associated with the progression-free survival of ECCA. We screened a key gene LSAMP from four genes using immunohistochemistry. The gene primarily participate in crucial biological processes such as the ECCA cell cycle and DNA replication. The qRT-PCR reaction and Western Blot conducted on the tissues provided confirmation of the expression levels of the gene, which exhibited consistency with the outcomes of our analysis. Our study has successfully identified potential biomarkers LSAMP for ECCA, which can serve as valuable tools for early detection and targeted therapeutic interventions in clinical settings.

Tackling triple negative breast cancer with HDAC inhibitors: 6 is the isoform!

Triple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by the lack in the expression of estrogen and progesterone receptors, and human epidermal growth factor receptors 2. TNBC stands out among other breast cancers subtypes for its high aggressiveness and invasiveness, and for the limited therapeutic options available, which justify the poor survival rates registered for this breast cancer subtype. Compelling new evidence pointed out the role of epigenetic modifications in cancer, prompting tumor cell uncontrolled proliferation, epithelial-to-mesenchymal transition, and metastatic events. In this review we showcase the latest evidence supporting the involvement of histone deacetylase 6 (HDAC6) in cancer pathways strictly related to TNBC subtype, also tracking the latest advancements in the identification of novel HDAC6 inhibitors which showed efficacy in TNBC models, offering insights into the potential of targeting this key epigenetic player as an innovative therapeutic option for the treatment of TNBC.

Glioblastoma Tumor Microenvironment: An Important Modulator for Tumoral Progression and Therapy Resistance.

The race to find an effective treatment for glioblastoma (GBM) remains a critical topic, because of its high aggressivity and impact on survival and the quality of life. Currently, due to GBM's high heterogeneity, the conventional treatment success rate and response to therapy are relatively low, with a median survival rate of less than 20 months. A new point of view can be provided by the comprehension of the tumor microenvironment (TME) in pursuance of the development of new therapeutic strategies to aim for a longer survival rate with an improved quality of life and longer disease-free interval (DFI). The main components of the GBM TME are represented by the extracellular matrix (ECM), glioma cells and glioma stem cells (GSCs), immune cells (microglia, macrophages, neutrophils, lymphocytes), neuronal cells, all of them having dynamic interactions and being able to influence the tumoral growth, progression, and drug resistance thus being a potential therapeutic target. This paper will review the latest research on the GBM TME and the potential therapeutic targets to form an up-to-date strategy.

MicroRNAs: emerging biomarkers and therapeutic targets in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant disease with high aggressiveness and a dismal prognosis, which is challenging to diagnose clinically early and gains low benefit from standard therapies. MicroRNAs (miRNAs) have become a hot topic in oncology research. Current evidence indicates that miRNAs are regulators involved in the entire process of PC, providing new diagnostic and therapeutic strategies for this fatal disease. Related research has been rapidly updated, making it necessary to review it to propose new directions and ideas and provide guidance for the development of precision medicine for PC. We reviewed the relevant literature through Pubmed, Embase, Web of Science and Medline, showing that abnormally expressed miRNAs in PC patients have the potential to be used as biomarkers for diagnosis and prognosis, highlighting the excellent prospect of combining miRNAs with traditional therapies, and the effective application of these factors for PC, especially miRNA mimics and inhibitors. MiRNAs participate in the entire process of PC and play important roles in diagnosis, treatment and prognosis. They are potential factors in conquering PC in the future.

Disulfidptosis-associated LncRNA signature predicts prognosis and immune response in kidney renal clear cell carcinoma

BackgroundKidney renal clear cell carcinoma (KIRC) represents a significant proportion of renal cell carcinomas and is characterized by high aggressiveness and poor prognosis despite advancements in immunotherapy. Disulfidptosis, a novel cell death pathway, has emerged as a critical mechanism in various cellular processes, including cancer. This study leverages machine learning to identify disulfidptosis-related long noncoding RNAs (DRlncRNAs) as potential prognostic biomarkers in KIRC, offering new insights into tumor pathogenesis and treatment avenues.ResultsOur analysis of data from The Cancer Genome Atlas (TCGA) led to the identification of 431 DRlncRNAs correlated with disulfidptosis-related genes. Five key DRlncRNAs (SPINT1-AS1, AL161782.1, OVCH1-AS1, AC131009.3, and AC108673.3) were used to develop a prognostic model that effectively distinguished between low- and high-risk patients with significant differences in overall survival and progression-free survival. The low-risk group had a favorable prognosis associated with a protective immune microenvironment and a better response to targeted drugs. Conversely, the high-risk group displayed aggressive tumor features and poor immunotherapy outcomes. Validation through qRT‒PCR confirmed the differential expression of these DRlncRNAs in KIRC cells compared to normal kidney cells, underscoring their potential functional significance in tumor biology.ConclusionsThis study established a robust link between disulfidptosis-related lncRNAs and patient prognosis in KIRC, underscoring their potential as prognostic biomarkers and therapeutic targets. The differential expression of these lncRNAs in tumor versus normal tissue further highlights their relevance in KIRC pathogenesis. The predictive model not only enhances our understanding of KIRC biology but also provides a novel stratification tool for precision medicine approaches, improving treatment personalization and outcomes in KIRC patients.

LINC01503 promotes the cell proliferation, migration and invasion of triple-negative breast cancer as a ceRNA to elevate SPNS2 expression by sponging miR-335–5p

ObjectiveTriple-negative breast cancer (TNBC) is a common cancer with high aggressiveness and high mortality in women. Recently, a plenty of studies have indicated that long non-coding RNAs (lncRNAs) exert the crucial function in human cancers, TNBC is included. The carcinogenicity of lncRNA long intergenic non-protein coding RNA 1503 (LINC01503) has been confirmed in several cancers, nevertheless, its function in TNBC still unclear. Therefore, our study aimed to reveal the underlying mechanism of LINC01503 in TNBC. MethodsIn our study, RT-qPCR was performed to detect the expression of LINC01503 in TNBC cells. The proliferative, invasive, migratory and apoptotic abilities of TNBC cells were detected by functional assay such as CCK-8, clone formation, EdU staining, transwell, and flow cytometry. RIP, RNA pull down, and luciferase assay revealed interactions between LINC01503, miR-335–5p, and sphingolipid transporter protein 2 (SPNS2). Finally, rescue experiments were performed to validate the previous results. ResultsLINC01503 expression was singularly high in TNBC cells. LINC01503 knockdown could restrain cell proliferation, invasion and migration, but accelerated cell apoptosis in TNBC. What’s more, miR-335–5p could be sponged by LINC01503 in TNBC. We also found that overexpressed miR-335–5p could inhibit cell proliferation, migration and invasion and facilitates cell apoptosis. Moreover, SPNS2 was the target gene of miR-335–5p and it functioned as an oncogene in TNBC cells. Finally, we found that overexpressed SPNS2 or inhibited miR-335–5p could reverse the suppressive function of silencing LINC01503 on TNBC progression. ConclusionLINC01503 could facilitate cell proliferation, migration and invasion of TNBC by sponging miR-335–5p to elevate SPNS2 expression.

Comparisons of magnetic resonance imaging, histopathological and Ki-67 labeling index findings in a single myxofibrosarcoma: a case report

BackgroundMyxofibrosarcoma is a myxoid soft tissue sarcoma showing T2 high intensity on magnetic resonance imaging. However, myxofibrosarcoma is a heterogeneous sarcoma with both myxoid and cellular portions. Magnetic resonance imaging findings were obtained MRI findings for comparison with histological and Ki-67 immunohistochemical features, in different portions of one myxofibrosarcoma.Case presentationMagnetic resonance imaging observations were compared with gross pathological and microscopic findings of a myxofibrosarcoma from a 50-year-old Japanese female. The Ki-67 labeling indices of different portions of the tumor, that is, the myxoid, cellular, and histologically confirmed infiltrative margin portions (pathological tail sign), were compared. The T2 low intensity area was more cellular than the T2 high intensity area, while the cellular portion had a significantly higher Ki-67 index than the myxoid portion (p = 0.0313). The portions with the pathological tail sign had a significantly higher Ki-67 labeling index than those without this sign (p = 0.0313).ConclusionsMore cellular portions of a myxofibrosarcoma correspond to more areas of the tumor showing aggressive features. Furthermore, our data also support the hypothesis of high aggressiveness being associated with the pathological tail sign in myxofibrosarcoma. To our knowledge, this is the first case report to describe comparisons among the imaging findings, histological features, and Ki-67 immunohistochemistry results for different portions of one myxofibrosarcoma.

A gut reaction? The role of the microbiome in aggression

Recent research has unveiled conflicting evidence regarding the link between aggression and the gut microbiome. Here, we compared behavior profiles of control, germ-free (GF), and antibiotic-treated mice, as well as re-colonized GF mice to understand the impact of the gut microbiome on aggression using the resident-intruder paradigm. Our findings revealed a link between gut microbiome depletion and higher aggression, accompanied by notable changes in urine metabolite profiles and brain gene expression. This study extends beyond classical murine models to humanized mice to reveal the clinical relevance of early-life antibiotic use on aggression. Fecal microbiome transplant from infants exposed to antibiotics in early life (and sampled one month later) into mice led to increased aggression compared to mice receiving transplants from unexposed infants. This study sheds light on the role of the gut microbiome in modulating aggression and highlights its potential avenues of action, offering insights for development of therapeutic strategies for aggression-related disorders.

Recent Advances in Immunotherapy for Breast Cancer: A Review.

Breast cancer is one of the most common malignant tumors in women in the world, and its incidence is increasing year by year, which seriously threatens the physical and mental health of women. Triple negative breast cancer (TNBC) is a special molecular type of breast cancer in which estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 are negative. Compared with other molecular types of breast cancer, triple-negative breast cancer (TNBC) has high aggressiveness and metastasis, high recurrence rate, lack of effective therapeutic targets, and usually poor clinical treatment effect. Chemotherapy was the main therapeutic means used in the past. With the advent of the immune era, immunotherapy has made a lot of progress in the treatment of triple-negative breast cancer (TNBC), bringing new therapeutic hope for the treatment of triple-negative breast cancer. This review combines the results of cutting-edge medical research, mainly summarizes the research progress of immunotherapy, and summarizes the main treatment methods of triple-negative breast cancer (TNBC) immunotherapy, including immune checkpoint inhibitors, tumor vaccines, adoptive immunotherapy and the application of traditional Chinese and western medicine. It provides a new idea for the treatment of triple negative breast cancer (TNBC).

Posttraumatic growth and psychopathological symptoms as predictors in the integration of North Korean adolescent refugees: Latent profile analysis.

This study is to explore identifiable psychological differences and predictors for the subgroup of refugees who at a very early age moved from a totalitarian country to a westernized democracy, ultimately to improve policies and reduce the maladaptation of refugees to a new society. More specifically, it is to fill in significant gaps in understanding and predicting refugee tendencies toward depression, social withdrawal, aggression, and posttraumatic growth. Latent class analysis was conducted to identify subgroups based on symptom profiles within a sample of 201 North Korean adolescent refugees residing in South Korea. Four subgroups were identified: (a) High growth, (b) Low trauma with high adaptive aggression, (c) Low trauma with high social withdrawal/depression, and (d) High trauma with high comorbidity. Predictors were physical health, self-esteem, peer support, teacher support, and school adjustment. Current refugee policies in South Korea would benefit from refining services to allow customization to the specific needs and characteristics of each adolescent rather than continue the current model of homogeneity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Deguelin inhibits the glioblastoma progression through suppressing CCL2/NFκB signaling pathway

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM.

Histone acetylation risk model predicts prognosis and guides therapy selection in glioblastoma: implications for chemotherapy and anti-CTLA-4 immunotherapy

BackgroundGlioblastoma is characterized by high aggressiveness, frequent recurrence, and poor prognosis. Histone acetylation-associated genes have been implicated in its occurrence and development, yet their predictive ability in glioblastoma prognosis remains unclear.ResultsThis study constructs a histone acetylation risk model using Cox and LASSO regression analyses to evaluate glioblastoma prognosis. We assessed the model’s prognostic ability with univariate and multivariate Cox regression analyses. Additionally, immune infiltration was evaluated using ESTIMATE and TIMER algorithms, and the SubMAP algorithm was utilized to predict responses to CTLA4 inhibitor. Multiple drug databases were applied to assess drug sensitivity in high- and low-risk groups. Our results indicate that the histone acetylation risk model is independent and reliable in predicting prognosis.ConclusionsLow-risk patients showed higher immune activity and longer overall survival, suggesting anti-CTLA4 immunotherapy suitability, while high-risk patients might benefit more from chemotherapy. This model could guide personalized therapy selection for glioblastoma patients.

Advances in two-photon absorption photodynamic therapy of glioma based on porphyrin-based metal-organicframework composites

Gliomas of the brain are characterised by high aggressiveness, high postoperative recurrence rate, high morbidity and mortality, posing a great challenge to clinical treatment. Traditional treatments include surgery, radiotherapy and chemotherapy; they also have significant associated side effects, leading to difficulties in tumour resection and recurrence. Photodynamic therapy has been shown to be a promising new strategy to help treat malignant tumours of the brain. It irradiates the tumour site at a specific wavelength to activate a photosensitiser, which selectively accumulates at the tumour site, triggering a photochemical reaction that destroys the tumour cells. It has the advantages of being minimally invasive, highly targeted and with few adverse reactions, and is expected to be well used in anti-tumour therapy. However, the therapeutic effect of traditional PDT is limited by the weak tissue penetration ability of photosensitiser, hypoxia and immunosuppression in the tumour microenvironment. This paper reviews the current research status on the therapeutic principle of photodynamic therapy in glioma and the mechanism of tumour cell injury, and also analyses the advantages and disadvantages of the current application in glioma treatment, and clarifies the analysis of ideas to improve the tissue penetration ability of photosensitizers. It aims to provide a feasible direction for the improvement of photodynamic therapy for glioma and a reference for the clinical treatment of deep brain tumours.

Clustering of methamphetamine users based on personality characteristics and self-efficacy in the west of Iran

With the substantial increase in the use of stimulants, especially methamphetamine, in recent years, the present study aimed to cluster methamphetamine users based on personality traits and self-efficacy, and compare their mental health, sleep quality, and the risk of relapse in the identified clusters. This cross-sectional study was conducted through convenience sampling on 501 methamphetamine users in addiction treatment centers in Kermanshah, western Iran. The data were collected using the Schwarzer General Self-Efficacy Scale, Zuckerman–Kuhlman Personality Questionnaire, Goldberg and Hiller General Health Questionnaire (GHQ), Zuckerman–Kuhlman Personality Questionnaire, and Stimulant Relapse Risk Scale (SRRS). A total of 501 methamphetamine users were distinguished into three clusters with frequencies of 111 (22.2%), 298 (59.5%), and 92 (18.4%) members through hierarchical cluster analysis. The participants in the first cluster were characterized by low self-efficacy, high neuroticism, sensation seeking, and aggressiveness, along with low extroversion and activity, low positive health, high negative health, low sleep quality, and high risk of drug relapse. The participants in the second cluster reported moderate levels of self-efficacy, neuroticism, sensation seeking, activity, and aggressiveness, high extroversion, and moderate levels of mental health, sleep quality, and the risk of relapse. Moreover, the participants in the third cluster reported the highest level of self-efficacy, the lowest level of neuroticism, sensation seeking, and aggressiveness, moderate extroversion and high activity, low relapse risk, high sleep quality, as well as high positive and low negative health symptoms. The third cluster was significantly different from the other two clusters in terms of the mentioned factors. The findings of this study suggest that low self-efficacy and the presence of neuroticism, sensation seeking, and high aggressiveness contribute to reduced mental health and sleep quality, as well as an increased risk of relapse in methamphetamine users.

Integrated multi-omics analysis and machine learning to refine molecular subtypes, prognosis, and immunotherapy in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) has a malignant characteristic that is highly aggressive and prone to metastasis. There is still a lack of suitable biomarkers to facilitate the refinement of precision-based therapeutic regimens. We used a combinationof10 known clustering algorithms and the omics data from 4 dimensions to identify high-resolution molecular subtypes of LUAD. Subsequently, consensus machine learning-related prognostic signature (CMRS) was developed based on subtypes related genes and an integrated program framework containing 10 machine learning algorithms. The efficiency of CMRS was analyzed from the perspectives of tumor microenvironment, genomic landscape, immunotherapy, drug sensitivity, and single-cell analysis. In terms of results,through multi-omics clustering, we identified 2 comprehensive omics subtypes (CSs) in which CS1 patients had worse survival outcomes, higher aggressiveness, mRNAsi and mutation frequency. Subsequently, we developed CMRS based on 13 key genes up-regulated in CS1. The prognostic predictive efficiency of CMRS was superior to most established LUAD prognostic signatures. CMRS demonstrated a strong correlation with tumor microenvironmental feature variants and genomic instability generation. Regarding clinical performance, patients in the high CMRS group were more likely to benefit from immunotherapy, whereas low CMRS were more likely to benefit from chemotherapy and targeted drug therapy. In addition, we evaluated that drugs such as neratinib, oligomycin A, and others may be candidates for patients in the high CMRS group. Single-cell analysis revealed that CMRS-related genes were mainly expressed in epithelial cells.The novel molecular subtypes identified in this study based on multi-omics data could provide new insights into the stratified treatment of LUAD, while the development of CMRS could serve as a candidate indicator of the degree of benefit of precision therapy and immunotherapy for LUAD.