An overview of the contemporary diagnosis and management approaches for anaplastic thyroid carcinoma.

Thyroid carcinoma is a complex disease with several types, the most common being well-differentiated and undifferentiated. The latter, "undifferentiated carcinoma", also known as anaplastic thyroid carcinoma (ATC), is a highly aggressive malignant tumor accounting for less than 0.2% of all thyroid carcinomas and carries a poor prognosis with a median survival of 5 months. BRAF gene mutations are the most common molecular factor associated with this type of thyroid carcinoma. Recent advances in targeted biological agents, immunotherapy, stem cell therapy, nanotechnology, the dabrafenib/trametinib combination therapy, immune checkpoint inhibitors (ICI) and artificial intelligence offer novel treatment options. The combination therapy of dabrafenib and trametinib is the current standard treatment for patients with BRAF-V600E gene mutations. Besides, the dabrafenib/trametinib combination therapy, ICI, used alone or in combination with targeted therapies have raised some hopes for improving the prognosis of this deadly disease. Younger age, earlier tumor stage and radiotherapy are all prognostic factors for improved outcomes. Ultimately, therapeutic regimens should be tailored to the individual patient based on surveillance and epidemiological data, and a multidisciplinary approach is essential.

New targets for cancer promotion and therapy in gliomas: Scinderin.

Glioma is one of the most common primary intracranial tumors, characterized by invasive growth and poor prognosis. Actin cytoskeletal rearrangement is an essential event in tumor cell migration. Scinderin (SCIN), an actin severing and capping protein that regulates the actin cytoskeleton, is involved in the proliferation and migration of certain cancer cells. However, its biological role and molecular mechanism in glioma remain unclear. Lin et al explored the role and mechanism of SCIN in gliomas. The results showed that SCIN mechanically affected cytoskeleton remodeling and inhibited the formation of lamellipodia via RhoA/FAK signaling pathway. This study identifies the cancer-promoting role of SCIN and provides a potential therapeutic target for SCIN in glioma treatment.

Cucurbitacin B targets STAT3 to induce ferroptosis in non-small cell lung cancer.

Cucurbitacin B (CuB) is a compound found in plants like Cucurbitaceae that has shown promise in fighting cancer, particularly in lung cancer. However, the specific impact of CuB on ferroptosis and how it works in lung cancer cells has not been fully understood. Our research has discovered that CuB can effectively slow down the growth of non-small cell lung cancer (NSCLC) cells. Even in small amounts, it was able to inhibit the growth of various NSCLC cell lines. This inhibitory effect was reversed when ferroptosis inhibitors DFO, Lip-1 and Fer-1 were introduced. CuB was found to increase the levels of reactive oxygen species (ROS), lipid ROS, MDA, and ferrous ions within H358 lung cancer cells, leading to a decrease in GSH, mitochondrial membrane potential (MMP) and changes in ferroptosis-related proteins in a dose-dependent manner. These findings were also confirmed in A549 lung cancer cells. In A549 cells, different concentrations of CuB induced the accumulation of intracellular lipid ROS, ferrous ions and changes in ferroptosis-related indicators in a concentration-dependent manner. Meanwhile, the cytotoxic effect induced by CuB in A549 cells was counteracted by ferroptosis inhibitors DFO and Fer-1. Through network pharmacology, we identified potential targets related to ferroptosis in NSCLC cells treated with CuB, with STAT3 targets showing high scores. Further experiments using molecular docking and cell thermal shift assay (CETSA) revealed that CuB interacts with the STAT3 protein. Western blot and immunofluorescence staining demonstrated that CuB inhibits the phosphorylation of STAT3 (P-STAT3) in H358 cells. Silencing STAT3 enhanced CuB-induced accumulation of lipid ROS and iron ions, as well as the expression of ferroptosis-related proteins. On the other hand, overexpression of STAT3 reversed the effects of CuB-induced ferroptosis. The results indicate that CuB has the capability to suppress STAT3 activation, resulting in ferroptosis, and could be a promising treatment choice for NSCLC.

Ferroptosis crosstalk in anti-tumor immunotherapy: molecular mechanisms, tumor microenvironment, application prospects.

Immunotherapies for cancer, specifically immune checkpoint inhibition (ICI), have shown potential in reactivating the body's immune response against tumors. However, there are challenges to overcome in addressing drug resistance and improving the effectiveness of these treatments. Recent research has highlighted the relationship between ferroptosis and the immune system within immune cells and the tumor microenvironment (TME), suggesting that combining targeted ferroptosis with immunotherapy could enhance anti-tumor effects. This review explores the potential of using immunotherapy to target ferroptosis either alone or in conjunction with other therapies like immune checkpoint blockade (ICB) therapy, radiotherapy, and nanomedicine synergistic treatments. It also delves into the roles of different immune cell types in promoting anti-tumor immune responses through ferroptosis. Together, these findings provide a comprehensive understanding of synergistic immunotherapy focused on ferroptosis and offer innovative strategies for cancer treatment.

Ferroptosis-Modulating Natural Products for Targeting Inflammation-Related Diseases: Challenges and Opportunities in Manipulating Redox Signaling.

Significance: Numerous disorders are linked to ferroptosis, a form of programmed cell death triggered by lipid peroxidation accumulation rather than apoptosis. Inflammation is the body's defensive response to stimuli and is also caused by inflammatory chemicals that can harm the body. The treatment of inflammatory diseases by focusing on the signaling pathways and mechanisms of ferroptosis has emerged as a new area worthy of extensive research. Recent Advances: Studies in cellular and animal models of inflammatory diseases have shown that ferroptosis markers are activated and lipid peroxidation levels are increased. Natural products (NPs) are gaining importance due to their ability to target ferroptosis pathways, particularly the Nuclear factor E2-related factor 2 signaling pathway, thereby suppressing inflammation and the release of pro-inflammatory cytokines. Critical Issues: This article provides an overview of ferroptosis, focusing on the signaling pathways and mechanisms connecting it to inflammation. It also explores the potential use of NPs as a treatment for inflammatory diseases and ferroptosis. Future Directions: NPs offer unique advantages, including multicomponent properties, multi-bio-targeting capabilities, and minimal side effects. Further research may facilitate the early clinical application of NPs to develop innovative treatment strategies.

A prognostic framework for predicting lung signet ring cell carcinoma via a machine learning based cox proportional hazard model.

PURPOSE: Signet ring cell carcinoma (SRCC) is a rare type of lung cancer. The conventional survival nomogram used to predict lung cancer performs poorly for SRCC. Therefore, a novel nomogram specifically for studying SRCC is highly required. METHODS: Baseline characteristics of lung signet ring cell carcinoma were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression and random forest analysis were performed on the training group data, respectively. Subsequently, we compared results from these two types of analyses. A nomogram model was developed to predict 1-year, 3-year, and 5-year overall survival (OS) for patients, and receiver operating characteristic (ROC) curves and calibration curves were used to assess the prediction accuracy. Decision curve analysis (DCA) was used to assess the clinical applicability of the proposed model. For treatment modalities, Kaplan-Meier curves were adopted to analyze condition-specific effects. RESULTS: We obtained 731 patients diagnosed with lung signet ring cell carcinoma (LSRCC) in the SEER database and randomized the patients into a training group (551) and a validation group (220) with a ratio of 7:3. Eight factors including age, primary site, T, N, and M.Stage, surgery, chemotherapy, and radiation were included in the nomogram analysis. Results suggested that treatment methods (like surgery, chemotherapy, and radiation) and T-Stage factors had significant prognostic effects. The results of ROC curves, calibration curves, and DCA in the training and validation groups demonstrated that the nomogram we constructed could precisely predict survival and prognosis in LSRCC patients. Through deep verification, we found the constructed model had a high C-index, indicating that the model had a strong predictive power. Further, we found that all surgical interventions had good effects on OS and cancer-specific survival (CSS). The survival curves showed a relatively favorable prognosis for T0 patients overall, regardless of the treatment modality. CONCLUSIONS: Our nomogram is demonstrated to be clinically beneficial for the prognosis of LSRCC patients. The surgical intervention was successful regardless of the tumor stage, and the Cox proportional hazard (CPH) model had better performance than the machine learning model in terms of effectiveness.

Feasibility and limitations of combined treatment for lateral pelvic lymph node metastases in rectal cancer.

Colorectal cancer ranks among the most commonly diagnosed cancers globally, and is associated with a high rate of pelvic recurrence after surgery. In efforts to mitigate recurrence, pelvic lymph node dissection (PLND) is commonly advocated as an adjunct to radical surgery. Neoadjuvant chemoradiotherapy (NACRT) is a therapeutic approach employed in managing locally advanced rectal cancer, and has been found to increase the survival rates. Chua et al have proposed a combination of NACRT with selective PLND for addressing lateral pelvic lymph node metastases in rectal cancer patients, with the aim of reducing recurrence and improving survival outcomes. Nevertheless, certain studies have indicated that the addition of PLND to NACRT and total mesorectal excision did not yield a significant reduction in local recurrence rates or improvement in survival. Consequently, meticulous patient selection and perioperative chemotherapy may prove indispensable in ensuring the efficacy of PLND.

TRAF6 Inhibitors from Marine Compound Library: Pharmacophore, Virtual Screening, Fragment Replacement, ADMET, and Molecular Dynamics.

TRAF6 is an E3 ubiquitin ligase that plays a crucial role in cell signaling. It is known that MMP is involved in tumor metastasis, and TRAF6 induces MMP-9 expression by binding to BSG. However, inhibiting TRAF6's ubiquitinase activity without disrupting the RING domain is a challenge that requires further research. To address this, we conducted computer-based drug screening to identify potential TRAF6 inhibitors. Using a ligand-receptor complex pharmacophore based on the inhibitor EGCG, known for its anti-tumor properties, we screened 52,765 marine compounds. After the molecular docking of 405 molecules with TRAF6, six compounds were selected for further analysis. By replacing fragments of non-binding compounds and conducting second docking, we identified two promising molecules, CMNPD9212-16 and CMNPD12791-8, with strong binding activity and favorable pharmacological properties. ADME and toxicity predictions confirmed their potential as TRAF6 inhibitors. Molecular dynamics simulations showed that CMNPD12791-8 maintained a stable structure with the target protein, comparable to EGCG. Therefore, CMNPD12791-8 holds promise as a potential inhibitor of TRAF6 for inhibiting tumor growth and metastasis.

Identification and experimental validation of immune-related gene PPARG is involved in ulcerative colitis.

BACKGROUND: The pathophysiology of ulcerative colitis (UC) is believed to be heavily influenced by immunology, which presents challenges for both diagnosis and treatment. The main aims of this study are to deepen our understanding of the immunological characteristics associated with the disease and to identify valuable biomarkers for diagnosis and treatment. METHODS: The UC datasets were sourced from the GEO database and were analyzed using unsupervised clustering to identify different subtypes of UC. Twelve machine learning algorithms and Deep learning model DNN were developed to identify potential UC biomarkers, with the LIME and SHAP methods used to explain the models' findings. PPI network is used to verify the identified key biomarkers, and then a network connecting super enhancers, transcription factors and genes is constructed. Single-cell sequencing technology was utilized to investigate the role of Peroxisome Proliferator Activated Receptor Gamma (PPARG) in UC and its correlation with macrophage infiltration. Furthermore, alterations in PPARG expression were validated through Western blot (WB) and immunohistochemistry (IHC) in both in vitro and in vivo experiments. RESULT: By utilizing bioinformatics techniques, we were able to pinpoint PPARG as a key biomarker for UC. The expression of PPARG was significantly reduced in cell models, UC animal models, and colitis models induced by dextran sodium sulfate (DSS). Interestingly, overexpression of PPARG was able to restore intestinal barrier function in H2O2-induced IEC-6 cells. Additionally, immune-related differentially expressed genes (DEGs) allowed for efficient classification of UC samples into neutrophil and mitochondrial metabolic subtypes. A diagnostic model incorporating the three disease-specific genes PPARG, PLA2G2A, and IDO1 demonstrated high accuracy in distinguishing between the UC group and the control group. Furthermore, single-cell analysis revealed that decreased PPARG expression in colon tissue may contribute to the polarization of M1 macrophages through activation of inflammatory pathways. CONCLUSION: In conclusion, PPARG, a gene related to immunity, has been established as a reliable potential biomarker for the diagnosis and treatment of UC. The immune response it controls plays a key role in the progression and development of UC by enabling interaction between characteristic biomarkers and immune infiltrating cells.

Honokiol suppress the PD-L1 expression to improve anti-tumor immunity in lung cancer.

Lung cancer is a serious health issue globally, and current treatments have proven to be inadequate. Therefore, immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway have become a viable treatment option in lun cancer. Honokiol, a lignan derived from Magnolia officinalis, has been found to possess anti-inflammatory, antioxidant, and antitumor properties. Our research found that honokiol can effectively regulate PD-L1 through network pharmacology and transcriptome analysis. Cell experiments showed that honokiol can significantly reduce PD-L1 expression in cells with high PD-L1 expression. Molecular docking, cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI)indicated that Honokiol can bind to PD-L1. Co-culture experiments on lung cancer cells and T cells demonstrated that honokiol mediates PD-L1 degradation, stimulates T cell activation, and facilitates T cell killing of tumor cells. Moreover, honokiol activates CD4 + and CD8 + T cell infiltration in vivo, thus suppressing tumor growth in C57BL/6 mice. In conclusion, this study has demonstrated that honokiol can inhibit the growth of lung cancer by targeting tumor cell PD-L1, suppressing PD-L1 expression, blocking the PD-1/PD-L1 pathway, and enhancing anti-tumor immunity.

The crosstalk between oncogenic signaling and ferroptosis in cancer.

Ferroptosis, a novel form of cell death regulation, was identified in 2012. It is characterized by unique features that differentiate it from other types of cell death, including necrosis, apoptosis, autophagy, and pyroptosis. Ferroptosis is defined by an abundance of iron ions and lipid peroxidation, resulting in alterations in subcellular structures, an elevation in reactive oxygen species (ROS), a reduction in glutathione (GSH) levels, and an augmentation in Fe (II) cytokines. Ferroptosis, a regulated process, is controlled by an intricate network of signaling pathways, where multiple stimuli can either enhance or hinder the process. This review primarily examines the defensive mechanisms of ferroptosis and its interaction with the tumor microenvironment. The analysis focuses on the pathways that involve AMPK, p53, NF2, mTOR, System Xc-, Wnt, Hippo, Nrf2, and cGAS-STING. The text discusses the possibilities of employing a combination therapy that targets several pathways for the treatment of cancer. It emphasizes the necessity for additional study in this field.

Mechanisms and potential applications of COPS6 in pan-cancer therapy.

The COP9 signalosome subunit 6 (COPS6) is abnormally overexpressed in many malignancies, yet its precise role in carcinogenesis is unknown. To gain a better understanding of COPS6's role, the authors conducted a pan-cancer analysis using various bioinformatics techniques such as differential expression patterns, prognostic value, gene mutations, immune infiltration, correlation analysis, and functional enrichment assessment. Results showed that COPS6 was highly correlated with prognosis, immune cell infiltration level, tumor mutation burden, and microsatellite instability in patients with a range of tumor types. This suggests that COPS6 may be a potential target for cancer treatment. Overall, this research provides insight into COPS6's role in cancer development and its potential therapeutic applications.

Role of targeting ferroptosis as a component of combination therapy in combating drug resistance in colorectal cancer.

Colorectal cancer (CRC) is a form of cancer that is often resistant to chemotherapy, targeted therapy, radiotherapy, and immunotherapy due to its genomic instability and inflammatory tumor microenvironment. Ferroptosis, a type of non-apoptotic cell death, is characterized by the accumulation of iron and the oxidation of lipids. Studies have revealed that the levels of reactive oxygen species and glutathione in CRC cells are significantly lower than those in healthy colon cells. Erastin has emerged as a promising candidate for CRC treatment by diminishing stemness and chemoresistance. Moreover, the gut, responsible for regulating iron absorption and release, could influence CRC susceptibility through iron metabolism modulation. Investigation into ferroptosis offers new insights into CRC pathogenesis and clinical management, potentially revolutionizing treatment approaches for therapy-resistant cancers.

Identifying ALOX15-initiated lipid peroxidation increases susceptibility to ferroptosis in asthma epithelial cells.

Ferroptosis is a programmed form of cell death regulated by iron and has been linked to the development of asthma. However, the precise mechanisms driving ferroptosis in asthma remain elusive. To gain deeper insights, we conducted an analysis of nasal epithelial and sputum samples from the GEO database using three machine learning methods. Our investigation identified a pivotal gene, Arachidonate 15-lipoxygenase (ALOX15), associated with ferroptosis in asthma. Through both in vitro and in vivo experiments, we further confirmed the significant role of ALOX15 in ferroptosis in asthma. Our results demonstrate that ferroptosis manifests in an HDM/LPS-induced allergic airway inflammation (AAI) mouse model, mimicking human asthma, and in HDM/LPS-stimulated 16HBE cells. Moreover, we observed an up-regulation of ALOX15 expression in HDM/LPS-induced mice and cells. Notably, silencing ALOX15 markedly decreased HDM/LPS-induced ferroptosis in 16HBE cells. These findings indicate that ferroptosis may be implicated in the onset and progression of asthma, with ALOX15-induced lipid peroxidation raising the susceptibility to ferroptosis in asthmatic epithelial cells.

Integration of transcriptomics and metabolomics identify biomarkers of aberrant lipid metabolism in ulcerative colitis.

BACKGROUND: The incidence of ulcerative colitis (UC) continues to rise globally, but effective therapeutic targets are still lacking. In recent years, numerous studies have indicated that lipid therapies could offer a novel perspective for UC treatment. Given the absence of prior research utilizing high-throughput data to identify target genes associated with lipid metabolism, we conducted this work. METHODS: The training set for this study was derived from four datasets within the Gene Expression Omnibus (GEO), encompassing a total of 357 UC patients. We employed four machine learning methods (LASSO, SVM, RF, and Boruta) to jointly identify core biomarkers in these patients, whose aberrant expression needed to be validated in independent datasets and in dextrose sulfate sodium salt (DSS)-induced UC mouse models. Regarding metabolomics, we detected abnormal oxidized lipids in the serum of UC mouse using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in conjunction with orthogonal partial least squares-discriminant analysis (OPLS-DA). RESULTS: Phospholipase A2 Group IIA (PLA2G2A) was first identified as a possible biomarker for UC, with AUC values of 0.810 and 1.000 in the two validation sets, while in animal models the gene showed similarly significant up-regulation in damaged intestinal mucosa. Further analysis of this gene showed that it was positively correlated with 17 immune cell types and histological severity. Additionally, we pioneered the development of a lipid metabolism score in UC research, which outperformed all individual genes in terms of disease diagnostic efficacy (AUC values of 0.980 and 1.000 for the two validation sets, respectively). Finally, the metabolomics study also identified 31 significantly abnormal oxidized lipids, including 12-HHT and DHA. CONCLUSIONS: PLA2G2A is a key therapeutic target for UC, and oxidized lipids such as 12-HHT can serve as potential serologic indicators for diagnosis.

Application of natural products in regulating ferroptosis in human diseases.

BACKGROUND: Ferroptosis is a type of cell death caused by excessive iron-induced peroxidation. It has been found to be involved in a variety of diseases, and natural products can be used to target ferroptosis in treatments. Natural products are biologically active compounds extracted or synthesized from nature. It is an important resource for the discovery of skeletons with a high degree of structural diversity and a wide range of bioactivities, which can be developed directly or used as a starting point for the optimization of new drugs. PURPOSE: In this review, we aim to discuss the interactions between natural products and ferroptosis in the treatment of human diseases. METHODS: Literature was searched in Pubmed, Science Direct, and Web of Science databases for the 11-year period from 2012 to 2023 using the search terms "natural products", "ferroptosis", "human disease", "neurodegenerative disease", "cardiovascular disease", and "cancer". RESULTS: In this research, the roles of natural products and ferroptosis were investigated. We suggest that natural products, such as terpenoids, flavonoids, polyphenols, alkaloids, and saponins, can be used in therapeutic applications for human diseases, as well as in ferroptosis. Additionally, the main mechanisms of ferroptosis were summarized and discussed. Furthermore, we propose that natural products can be utilized to enhance the sensitivity of cancer cells to ferroptosis, thus helping to overcome drug resistance and inhibit metastasis. Moreover, natural products have the potential to modulate the expression levels of ferroptosis-related factors. Finally, the future directions of this field were highlighted. CONCLUSION: The potential of natural products which focus on ferroptosis to treat human illnesses, particularly cancer, is very encouraging for human wellbeing.

In silico analysis of small molecule compounds based on pharmacophore- and backbone-leaping peroxiredoxin 1 (PRDX1) inhibitors.

Abnormal expression of PRDX has been found to play a significant role in the growth of colorectal cancer and other types of tumors. Despite the identification of several PRDX1 inhibitory compounds in recent years, none of them have been utilized in clinical treatments. Therefore, we conducted a virtual screening of 210,331 small molecules from the SPECS library using PRDX1 and multiple methods. From this screening, we identified 13 compounds with the highest scores from the molecular docking analysis. To further validate the accuracy of our pharmacophore model, we constructed a structure-based pharmacophore model and analyzed the receiver operating characteristic curve (ROC curve). Through this process, we selected nine compounds using skeleton jumping and virtual screening based on the highest pharmacophore model scores. Subsequently, we examined the ADMET properties of these nine compounds to assess their drug-forming potential, resulting in three compounds with the best drug properties. Finally, we assessed the binding stability of these three candidate molecules to proteins using molecular dynamics and MM-PBSA calculations. After a comprehensive evaluation, we found that compounds 6 and 9 formed stable complexes with PRDX1 proteins and could potentially serve as competitive inhibitors of PRDX1 substrates.Communicated by Ramaswamy H. Sarma.

TM9SF1 is implicated in promoting the proliferation and invasion of bladder cancer cells.

Zhuo et al looked into the part of transmembrane 9 superfamily member 1 (TM9SF1) in bladder cancer (BC), and evaluated if it can be used as a therapeutic target. They created a permanent BC cell line and tested the effects of TM9SF1 overexpression and suppression on BC cell growth, movement, invasion, and cell cycle advancement. Their results show that TM9SF1 can boost the growth, movement, and invasion of BC cells and their access into the G2/M stage of the cell cycle. This research gives a novel direction and concept for targeted therapy of BC.

Identification of PLK1-PBD Inhibitors from the Library of Marine Natural Products: 3D QSAR Pharmacophore, ADMET, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study.

PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create new inhibitors for the PLK1-PBD by focusing on the PBD binding domain, which has the potential for greater selectivity. A 3D QSAR model was developed using a dataset of 112 compounds to evaluate 500 molecules. ADMET prediction was then used to select three molecules with strong drug-like characteristics. Scaffold hopping was employed to reconstruct 98 new compounds with improved drug-like properties and increased activity. Molecular docking was used to compare the efficient compound abbapolin, confirming the high-activity status of [(14S)-14-hydroxy-14-(pyridin-2-yl)tetradecyl]ammonium,[(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium. Molecular dynamics simulations and MMPBSA were conducted to evaluate the stability of the compounds in the presence of proteins. An in-depth analysis of [(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium identified them as potential candidates for PLK1 inhibitors.