Targeting anoikis resistance as a strategy for cancer therapy.

Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to evade anoikis, e.g. anoikis resistance, thereby allowing for cells to survive under anchorage-independent conditions. Uncovering the mechanisms of anoikis resistance will provide details about cancer metastasis, and potential strategies against cancer cell dissemination and metastasis. Here, we summarize the principal elements and core molecular mechanisms of anoikis and anoikis resistance. We discuss the latest progress of how anoikis and anoikis resistance are regulated in cancers. Furthermore, we summarize emerging data on selective compounds and nanomedicines, explaining how inhibiting anoikis resistance can serve as a meaningful treatment modality against cancers. Finally, we discuss the key limitations of this therapeutic paradigm and possible strategies to overcome them. In this review, we suggest that pharmacological modulation of anoikis and anoikis resistance by bioactive compounds could surmount anoikis resistance, highlighting a promising therapeutic regimen that could be used to overcome anoikis resistance in cancers.

Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers.

Drug resistance in cancer remains a major challenge in oncology, impeding the effectiveness of various treatment modalities. The nuclear factor-kappa B (NF-κB) signaling pathway has emerged as a critical player in the development of drug resistance in cancer cells. This comprehensive review explores the intricate relationship between NF-κB and drug resistance in cancer. We delve into the molecular mechanisms through which NF-κB activation contributes to resistance against chemotherapeutic agents, targeted therapies, and immunotherapies. Additionally, we discuss potential strategies to overcome this resistance by targeting NF-κB signaling, such as small molecule inhibitors and combination therapies. Understanding the multifaceted interactions between NF-κB and drug resistance is crucial for the development of more effective cancer treatment strategies. By dissecting the complex signaling network of NF-κB, we hope to shed light on novel therapeutic approaches that can enhance treatment outcomes, ultimately improving the prognosis for cancer patients. This review aims to provide a comprehensive overview of the current state of knowledge on NF-κB and its role in drug resistance, offering insights that may guide future research and therapeutic interventions in the fight against cancer.

crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.

AIMS: With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear. METHODS: An in vivo shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents. RESULTS: VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model. CONCLUSION: This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.

Methylation of GPRC5A promotes liver metastasis and docetaxel resistance through activating mTOR signaling pathway in triple negative breast cancer.

AIMS: This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance and liver metastasis of breast cancer. METHODS: Single-cell RNA transcriptomic analysis and bioinformatic analysis are used to screen relevant genes in breast cancer metastatic hepatic specimens. MeRIP, dual-luciferase analysis and bioinformation were used to detect m6A modulation. Mass spectrometry (MS), co-inmunoprecipitation (co-IP) and immunofluorescence colocalization were executed to explore the mechanism of GPRC5A in breast cancer cells. RESULT: GPRC5A was upregulated in triple-negative breast cancer (TNBC) and was associated with a poor prognosis. In vitro and in vivo experiments demonstrated that knockdown of GPRC5A alleviated metastasis and resistance to docetaxel in TNBC. Overexpression of GPRC5A had the opposite effects. The m6A methylation of GPRC5A mRNA was modulated by METTL3 and YTHDF1, which facilitates its translation. GPRC5A inhibited the ubiquitination-dependent degradation of LAMTOR1, resulting in the recruitment of mTORC1 to lysosomes and activating the mTORC1/p70s6k signaling pathway. CONCLUSION: METTL3/YTHDF1 axis up-regulates GPRC5A expression by m6A methylation. GPRC5A activates mTORC1/p70s6k signaling pathway by recruiting mTORC1 to lysosomes, consequently promotes docetaxel-resistance and liver metastasis.

JAK/STAT in leukemia: a clinical update.

Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.

Nasopharyngeal carcinoma: current views on the tumor microenvironment's impact on drug resistance and clinical outcomes.

The incidence of nasopharyngeal carcinoma (NPC) exhibits significant variations across different ethnic groups and geographical regions, with Southeast Asia and North Africa being endemic areas. Of note, Epstein-Barr virus (EBV) infection is closely associated with almost all of the undifferentiated NPC cases. Over the past three decades, radiation therapy and chemotherapy have formed the cornerstone of NPC treatment. However, recent advancements in immunotherapy have introduced a range of promising approaches for managing NPC. In light of these developments, it has become evident that a deeper understanding of the tumor microenvironment (TME) is crucial. The TME serves a dual function, acting as a promoter of tumorigenesis while also orchestrating immunosuppression, thereby facilitating cancer progression and enabling immune evasion. Consequently, a comprehensive comprehension of the TME and its intricate involvement in the initiation, progression, and metastasis of NPC is imperative for the development of effective anticancer drugs. Moreover, given the complexity of TME and the inter-patient heterogeneity, personalized treatment should be designed to maximize therapeutic efficacy and circumvent drug resistance. This review aims to provide an in-depth exploration of the TME within the context of EBV-induced NPC, with a particular emphasis on its pivotal role in regulating intercellular communication and shaping treatment responses. Additionally, the review offers a concise summary of drug resistance mechanisms and potential strategies for their reversal, specifically in relation to chemoradiation therapy, targeted therapy, and immunotherapy. Furthermore, recent advances in clinical trials pertaining to NPC are also discussed.

Discovery of vitexin as a novel VDR agonist that mitigates the transition from chronic intestinal inflammation to colorectal cancer.

Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.

CircXPO6 promotes breast cancer progression through competitively inhibiting the ubiquitination degradation of c-Myc.

The number of breast cancer (BC) patients is increasing year by year, which is severely endangering to human life and health. c-Myc is a transcription factor, studies have shown that it is a very significant factor in tumor progression, but how it is regulated in BC is still not well understood. Here, we used the RIP microarray sequencing to confirm circXPO6, which had a high affinity with c-Myc and highly expressed in triple-negative breast cancer (TNBC) tissues and cells. CircXPO6 overexpression promoted tumor growth in vivo and in vitro. Furthermore, circXPO6 largely promoted the expression of genes related to glucose metabolism, such as GLUT1, HK2, and MCT4 in TNBC cells. Finally, high levels of circXPO6 expression were found to be closely associated with malignant pathological factors, such as tumor size, lymph node metastasis, TNM staging, and histopathological grading of TNBC. Mechanistically, circXPO6 interacted with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation, thus promoting TNBC progression. Through the regulation of c-Myc-mediated signal transduction, circXPO6 plays a key role in TNBC progresses. This discovery can provide new ideas for TNBC molecular targeted therapy.

Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy.

AIMS: This study aims at investigating the role of a neighbor long non-coding RNA (lncRNA) of HDAC4 (LOC85009) in docetaxel (DTX) resistance of lung adenocarcinoma (LUAD). METHODS: RT-qPCR was used to analyze LOC85009 expression in DTX-resistant LUAD cells. In vitro and in vivo experiments were applied to detect the influence of LOC85009 on LUAD cell growth and xenograft tumor growth. DNA pull down assay, RNA pull down assay, ChIP assay, CoIP assay and RIP assay were performed to identify the direct interactions between factors. RESULTS: LOC85009 was lowly-expressed in DTX-resistant LUAD cells. Functionally, LOC85009 overexpression inhibited DTX resistance and cell proliferation but triggered cell apoptosis. Moreover, we identified that LOC85009 was transferred from LUAD cells to DTX-resistant LUAD cells via exosomes. Exosomal LOC85009 inhibited DTX resistance, proliferation and autophagy while induced apoptosis in DTX-resistant cells. Additionally, we found that LOC85009 sequestered ubiquitin-specific proteinase 5 (USP5) to destabilize upstream transcription factor 1 (USF1) protein, thereby inactivating ATG5 transcription. CONCLUSIONS: Exosomal LOC85009 inhibits DTX resistance through regulation of ATG5-induced autophagy via USP5/USF1 axis, suggesting that LOC85009 might be a potential target to reverse DTX resistance in the treatment of LUAD.

Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer.

Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.

Multi-omic and comparative analyses revealed monocyte-derived alpha-defensin-1 correlated with COVID-19 severity and inhibited SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological pathogen of coronavirus disease 2019 (COVID-19), a highly contagious disease, spreading quickly and threatening global public health. The symptoms of COVID-19 vary from mild reactions to severe respiratory distress or even fatal outcomes probably due to the different status of host immunity against the virus. Here in the study, we unveiled plasma proteomic signatures and transcriptional patterns of peripheral blood mononuclear cells (PBMCs) using blood samples of 10 COVID-19 patients with different severity. Through systemic analysis, α-defensin-1 (DEFA1) was identified to be elevated in both plasma and PBMCs, and correlated with disease severity and stages. In vitro study demonstrated that DEFA1 was secreted from immunocytes and suppressed SARS-CoV-2 infection of both original and mutated strains with dose dependency. By using sequencing data, we discovered that DEFA1 was activated in monocytes through NF-κB signaling pathway after infection, and secreted into circulation to perturb SARS-CoV-2 infection by interfering protein kinase C expression. It worked mainly during virus replication instead of entry in host cells. Together, the anti-SARS-CoV-2 mechanism of DEFA1 has unveiled a corner of how innate immunity is against SARS-CoV-2 and explored its clinical potential in disease prognosis and therapeutic intervention.

Single-cell histone chaperones patterns guide intercellular communication of tumor microenvironment that contribute to breast cancer metastases.

BACKGROUND: Histone chaperones (HCs) are crucial for governing genome stability and gene expression in multiple cancers. However, the functioning of HCs in the tumor microenvironment (TME) is still not clearly understood. METHODS: Self-tested single-cell RNA-seq data derived from 6 breast cancer (BC) patients with brain and liver metastases were reanalyzed by nonnegative matrix factorization (NMF) algorithm for 36 HCs. TME subclusters were observed with BC and immunotherapy public cohorts to assess their prognosis and immune response. The biological effect of HSPA8, one of the HCs, was verified by transwell assay and wound-healing assays. RESULTS: Cells including fibroblasts, macrophages, B cells, and T cells, were classified into various subclusters based on marker genes. Additionally, it showed that HCs might be strongly associated with biological and clinical features of BC metastases, along with the pseudotime trajectory of each TME cell type. Besides, the results of bulk-seq analysis revealed that TME cell subclusters mediated by HCs distinguished significant prognostic value for BC patients and were relevant to patients' immunotherapy responses, especially for B cells and macrophages. In particular, CellChat analysis exhibited that HCs-related TME cell subclusters revealed extensive and diverse interactions with malignant cells. Finally, transwell and wound-healing assays exhibited that HSPA8 deficiency inhibited BC cell migration and invasion. CONCLUSIONS: Collectively, our study first dissected HCs-guided intercellular communication of TME that contribute to BC metastases.

tRNA-derived fragments in gastric cancer: Biomarkers and functions.

tRNA-derived fragments (tRFs), non-coding RNAs that regulate protein expression after transcription, have recently been identified as potential biomarkers. We identified differentially expressed tRFs in gastric cancer (GC) and the biological properties of tRFs in predicting the malignancy status of GCs as possible biomarkers. Until 15 February 2022, two independent reviewers did a thorough search in electronic databases of Scopus, EMBASE and PubMed. The QUADAS scale was used for quality assessment of the included studies. Ten articles investigating the clinical significance of tRFs, including 928 patients, were analysed. In 10 GC studies, seven tRFs were considerably upregulated and five tRFs were significantly downregulated when compared to controls. Risk of bias was rated low for index test, and flow as well as timing domains in relation to the review question. The applicability of the index test, flow and timing and patient selection for 10 studies was deemed low. In this study, we review the advances in the study of tRFs in GC and describe their functions in gene expression regulation, such as suppression of translation, cell differentiation, proliferation and the related signal transduction pathways associated with them. Our findings may offer researchers new ideas for cancer treatment as well as potential biomarkers for further research in GC.

The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition.

BACKGROUND: Metastasis of breast cancer have caused the majority of cancer-related death worldwide. The circRNAs are associated with tumorigenesis and metastasis in breast cancer according to recent research. However, the biological mechanism of circRNAs in liver metastatic breast cancer remains ambiguous yet. METHODS: Microarray analysis of three pairs of primary BC tissues and matched hepatic metastatic specimens identified circEZH2. We used RT-qPCR and FISH assays to confirm circEZH2 existence, characteristics, and expression. Both in vivo and in vitro, circEZH2 played an oncogenic role which promoted metastasis as well. A range of bioinformatic analysis, Western blot, RNA pull-down, RIP, ChIP, and animal experiments were used to define the feedback loop involving FUS, circEZH2, miR-217-5p, KLF5, FUS, CXCR4 as well as epithelial and mesenchymal transition. RESULTS: In our research, circEZH2 was proved to be upregulated in liver metastases in BC and predicted the worse prognosis in breast cancer patients. Overexpression of circEZH2 notably accentuated the vitality and invasion of BC cells, whereas knockdown of circEZH2 elicited the literally opposite effects. Besides, overexpressed circEZH2 promoted tumorigenesis and liver metastasis in vivo. Moreover, circEZH2 could adsorb miR-217-5p to upregulate KLF5 thus leading to activate FUS transcription which would facilitate the back-splicing program of circEZH2. Meanwhile, KLF5 could upregulated CXCR4 transcriptionally to accelerate epithelial and mesenchymal transition of breast cancer. CONCLUSIONS: Consequently, a novel feedback loop FUS/circEZH2/KLF5/CXCR4 was established while circEZH2 could be novel biomarker and potential target for BC patients' therapy.

The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin.

BACKGROUND: Metastasis causes the majority of cancer-related deaths worldwide. Increasing studies have revealed that circRNAs are associated with the carcinogenesis and metastasis of many cancers. Nevertheless, the biological mechanisms of circRNAs in breast cancer (BC) liver metastasis remain extremely ambiguous. METHODS: In this study, we identified circROBO1 from three pairs of primary BC and metastatic liver sites by RNA sequencing. FISH assays and RT-qPCR were conducted to validate the existence and expression of circROBO1. The oncogenic role of circROBO1 was demonstrated both in vitro and in vivo. Western blot, ChIP, RIP, RNA pull-down, and dual-luciferase reporter assays were used to confirm the interaction of the feedback loop among circROBO1, miR-217-5p, KLF5, and FUS. Meanwhile, the regulation of selective autophagy was investigated by immunofluorescence, CoIP, and western blot. RESULTS: In this study, upregulated expression of circROBO1 was found in BC-derived liver metastases and was correlated with poor prognosis. Knockdown of circROBO1 strikingly inhibited the proliferation, migration, and invasion of BC cells, whereas overexpression of circROBO1 showed the opposite effects. Moreover, overexpression of circROBO1 promoted tumor growth and liver metastasis in vivo. Further research revealed that circROBO1 could upregulate KLF5 by sponging miR-217-5p, allowing KLF5 to activate the transcription of FUS, which would promote the back splicing of circROBO1. Therefore, a positive feedback loop comprising circROBO1/KLF5/FUS was formed. More importantly, we found that circROBO1 inhibited selective autophagy of afadin by upregulating KLF5. CONCLUSIONS: Our results demonstrated that circROBO1 facilitates the carcinogenesis and liver metastasis of BC through the circROBO1/KLF5/FUS feedback loop, which inhibits the selective autophagy of afadin by suppressing the transcription of BECN1. Therefore, circROBO1 could be used not only as a potential prognostic marker but also as a therapeutic target in BC.

Identification of clinical candidates against West Nile virus by activity screening in vitro and effect evaluation in vivo.

The West Nile virus (WNV) is a member of the flavivirus and is known to cause encephalitis. There is currently no specific treatment for WNV infection. Repurposing of clinically approved drugs appeared promising for rapidly identifying effective, safe, and readily available candidates for antiviral drugs. Here, we screened the small-molecule compounds with anti-WNV activity from 978 Food Drug Administration-approved drugs. Four compounds, including cilnidipine, mycophenolate mofetil, nitazoxanide, and teriflunomide, were found to efficiently abrogate WNV infection in Vero cells and human neuroblastoma SH-SY5Y cells. The four compounds also exert broad-spectrum antiviral activity against the Zika virus, Japanese encephalitis virus, yellow fever virus, tick-borne encephalitis virus, and chikungunya virus. Furthermore, nitazoxanide (a synthetic benzamide) and teriflunomide (an inhibitor of dihydroorotate dehydrogenase, DHODH) protected 20% and 40% of mice from lethal WNV challenge, respectively. Both drugs, which are orally bioavailable and have been approved clinically for many years, may be promising therapeutics for WNV infection. Moreover, the other two DHODH inhibitors, ML390 and vidofludimus, also displayed potent activity against WNV infection in vitro and in vivo.

Antiviral efficacy of selective estrogen receptor modulators against SARS-CoV-2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh member of the coronavirus family that can infect humans. Recently, more contagious and pathogenic variants of SARS-CoV-2 have been continuously emerging. Clinical candidates with high efficacy and ready availability are still in urgent need. To identify potent anti-SARS-CoV-2 repurposing drugs, we evaluated the antiviral efficacy of 18 selective estrogen receptor modulators (SERMs) against SARS-CoV-2 infection. Six SERMs exhibited excellent anti-SARS-CoV-2 effects in Vero E6 cells and three human cell lines. Clomifene citrate, tamoxifen, toremifene citrate, and bazedoxifene acetate reduced the weight loss of hamsters challenged with SARS-CoV-2, and reduced hamster pulmonary viral load and interleukin-6 expression when assayed at 4 days postinfection. In particular, bazedoxifene acetate was identified to act on the penetration stage of the postattachment step via altering cholesterol distribution and endosome acidification. And, bazedoxifene acetate inhibited pseudoviruses infection of original SARS-CoV-2, Delta variant, Omicron variant, and SARS-CoV. These results offer critical information supporting bazedoxifene acetate as a promising agent against coronaviruses.

Synthesis of baicalein derivatives and evaluation of their antiviral activity against arboviruses.

Natural plant-derived baicalein which is extracted from Chinese herb Scutellaria baicalensis Georgi belongs to the flavonoid compounds and possesses multiple pharmacological activities. In this study, we designed and synthesized new series of derivatives of baicalein (BE) through catalytic coupling reactions, and screened for their antiviral activity against arboviruses including Chikungunya virus (CHIKV), West Nile virus (WNV) or Zika virus (ZIKV). Our results revealed for the first time that BE and its derivatives had potent anti-CHIKV, anti-WNV and anti-ZIKV effects. And modification of 8 or 4' position could lead to obtain potent antiviral compounds against CHIKV, WNV and ZIKV with lower cytotoxicity. Among the baicalein derivatives, C3 and F3 showed the most potent antiviral activities against CHIKV, WNV and ZIKV, which were 5-10 times more potent than baicalein. Our findings will provide research basis for the development of baicalein derivatives as effective antiviral agents.

Identification of a prognostic metabolic gene signature in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a clinically diverse disease. Given the numerous genetic mutations and variations associated with it, a prognostic gene signature that can be related to the overall survival (OS) is a clinical implication. We used the mRNA expression profiles and clinicopathological data of patients with DLBCL from the Gene Expression Omnibus (GEO) database to identify a metabolism-related gene signature. Using LASSO regression analysis, a novel 13-metabolic gene signature was identified to evaluate prognosis. The information gathered was used to construct the nomogram model to improve risk stratification and quantify risk factors for individual patients. We performed gene set enrichment analysis to identify the enriched signalling axes to further understand the underlying biological pathways. The receiver operating characteristic (ROC) curve revealed a satisfactory performance in the training cohorts. The model also showed clinical benefit when compared to the standard prognostic factors (P < .05) in validation cohorts. This study aimed to combine metabolic dysregulation with clinical features of patients with DLBCL to generate a prognostic model that might not only indicate the value of the metabolic microenvironment for prognostic stratification but also improve the decision-making during individual therapy.

Establishment of a prognostic ferroptosis-related gene profile in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a heterogeneous disease with a difficult to predict prognosis. Ferroptosis, an iron-induced programmed cell death, is a promising target for cancer therapy. Nevertheless, not much is known about the relationship between ferroptosis-related genes and AML prognosis. Herein, we retrieved RNA profile and corresponding clinical data of AML patients from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Univariate Cox analysis was employed to identify ferroptosis-related genes significantly associated with AML prognosis. Next, the least absolute shrinkage and selection operator (LASSO) regression was employed to establish a prognostic ferroptosis-related gene profile. 12 ferroptosis-related genes were screened to generate a prognostic model, which stratified patients into a low- (LR) or high-risk (HR) group. Using Kaplan-Meier analysis, we demonstrated that the LR patients exhibited better prognosis than HR patients. Moreover, receiver operating characteristic (ROC) curve analysis confirmed that the prognostic model showed good predictability. Functional enrichment analysis indicated that the infiltration of regulatory T cells (Treg) differed vastly between the LR and HR groups. Our prognostic model can offer guidance into the accurate prediction of AML prognosis and selection of personalized therapy in clinical practice.