Apatinib is a targeted therapy used in the treatment of advanced gastric cancer. However, many gastric cancer patients develop resistance to Apatinib, and the mechanisms underlying this resistance remain unclear. Previous studies have shown that Apatinib can induce ferroptosis in gastric cancer cells. More recent research suggests that polyunsaturated ether phospholipids are closely associated with tumor cell sensitivity to ferroptosis, and may represent key molecules involved in the resistance of tumor cells to ferroptosis.

We established Apatinib-resistant gastric cancer cell lines and assessed their tolerance to ferroptosis. We identified key enzymes responsible for the ferroptosis tolerance observed in drug-resistant cells using lipidomics and transcriptomics analysis. Molecular and biological experiments were conducted to elucidate the molecular mechanisms underlying Apatinib resistance mediated by ferroptosis tolerance in gastric cancer cells.

Apatinib resistance is closely linked to ferroptosis resistance, which is driven by a reduction in the levels of polyunsaturated ether phospholipids-phospholipids that are particularly susceptible to oxidation and induce ferroptosis. The downregulation of key enzymes involved in polyunsaturated ether phospholipid synthesis, such as AGPS, mediates tolerance to both ferroptosis and Apatinib in gastric cancer cells, both in vitro and in vivo. Mechanistically, the expression of AGPS in tumor cells is regulated by the transcription factor ELK1. Drug-resistant cells acquire Apatinib tolerance by downregulating both ELK1 and AGPS expression.

Apatinib-resistant gastric cancer cells exhibit reduced expression of the transcription factor ELK1, which regulates the expression of AGPS. This reduction contributes to the resistance and malignancy of gastric cancer cells.

We have previously demonstrated that GLUT1 can interact with phosphorylated EGFR and has an oncogenic role in lung cancer. Here, we aim to investigate their binding region and its signaling pathways.

The AlphaFold 3 prediction, Co-immunoprecipitation, and Western blot were used to uncover the interaction conditions of GLUT1 and EGFR. The RNA-seq data was analyzed to evaluate the difference in signaling pathways between wild-type EGFR and activated mutated EGFR. The xenograft tumor model was established to determine the therapy effect of the combination of GLUT1 inhibitor BAY-876 and EGFR TKI Osimertinib.

We found that the interaction ability of GLUT1 and EGFR depended on the activation of EGFR. GLUT1 interacted with EGFRvIII (loss 2-7 exons) but not with EGFRvI (loss 1-16 exons), so GLUT1 interacts with EGFR in the EGFR extracellular transmembrane region. GLUT1 regulated EGFR downstream signaling pathways. GLUT1 inhibitor BAY-876 can sensitize tumor cells to EGFR TKI Osimertinib.

GLUT1 participates in tumor progression by interacting with phosphor-EGFR, suggesting that inhibition of the GLUT1-EGFR axis may be a potential therapeutic strategy for lung cancer treatment.

This comprehensive review delves into the pivotal role of intestinal epithelial cells in the context of various diseases. It provides an in-depth analysis of the diverse types and functions of these cells, explores the influence of multiple signaling pathways on their differentiation, and elucidates their critical roles in a spectrum of diseases. The significance of the gastrointestinal tract in maintaining overall health is extremely important and cannot be exaggerated. This complex and elongated organ acts as a crucial link between the internal and external environments, making it vulnerable to various harmful influences. Preserving the normal structure and function of the gut is essential for well-being. Intestinal epithelial cells serve as the primary defense mechanism within the gastrointestinal tract and play a crucial role in preventing harmful substances from infiltrating the body. As the main components of the digestive system, they not only participate in the absorption and secretion of nutrients and the maintenance of barrier function but also play a pivotal role in immune defense. Therefore, the health of intestinal epithelial cells is of vital importance for overall health.

Changes in cell signaling pathways, which in normal conditions determine the maintenance of cell homeostasis and the correctness of its basic processes, may cause the transformation of a normal cell into a cancer cell. Alterations in cellular metabolism leading to oncogenesis are considered to be a hallmark of cancer cells. Therefore, a thorough understanding of cellular enzymes affecting metabolism and respiration, as well as intracellular pathways connected with them, seems crucial. These changes may be both prognostic and predictive factors, especially in terms of using molecularly targeted therapies. Aberrations in the pathways responsible for cell growth and angiogenesis are considered particularly important in the process of oncogenesis. Gliomas are the most common primary malignant tumors of the brain. The most important molecular disorders determining their particularly malignant nature are aberrations in the pathways responsible for cell growth and angiogenesis, such as the PI3K/Akt or RAS/MAPK/ERK signaling pathway, as well as excessive activity of enzymes, like hexokinases, which play a key role in glycolysis, autophagy, and apoptosis. The multitude of alterations detected in glioma cells, high heterogeneity, and the immunosuppressive environment within the tumor are the main features causing failures in the attempts to implement modern therapies.

Acute myeloid leukemia (AML) is a severe hematological malignancy characterized by high recurrence rates, especially in pediatric patients, highlighting the need for reliable prognostic markers. This study proposes methylation signatures associated with AML recurrence using computational methods. DNA methylation data from 696 newly diagnosed and 194 relapsed pediatric AML patients were analyzed. Feature selection algorithms, including Boruta, least absolute shrinkage and selection operator, light gradient boosting machine, and Monte Carlo feature selection, were employed to screen and rank methylation sites strongly correlated with AML recurrence. Incremental Feature Selection was performed to evaluate these results, and optimal subsets were identified using Decision Tree and Random Forest methods. Several important methylation features, such as modifications in SLC45A4, S100PBP, TSPAN9, PTPRG, ERBB4, and PRKCZ, emerged from the intersection of all feature selection algorithms. Functional enrichment analysis indicated these genes participate in biological processes, including calcium-mediated signaling and regulation of binding. These findings are consistent with existing literature, suggesting that identified methylation features likely contribute to AML progression through alterations in gene expression levels. Therefore, this study provides a valuable reference for enhancing recurrence risk prediction models in AML and clarifying disease pathogenesis, as well as offering broader insights into mechanisms underlying other major diseases.

Latest advances in super-resolution microscopy allow the study of subcellular features at the level of single proteins, which could lead to discoveries in fundamental biological processes, specifically in cell signaling mediated by membrane receptors. Despite these advances, accurately extracting quantitative information on molecular arrangements of proteins at the 1-20 nm scale through rigorous image analysis remains a significant challenge. Here, we present SPINNA (Single-Protein Investigation via Nearest-Neighbor Analysis): an analysis framework that compares nearest-neighbor distances from experimental single-protein position data with those obtained from realistic simulations based on a user-defined model of protein oligomerization states. We demonstrate SPINNA in silico, in vitro, and in cells. In particular, we quantitatively assess the oligomerization of the epidermal growth factor receptor (EGFR) upon EGF treatment and investigate the dimerization of CD80 and PD-L1, key surface ligands involved in immune cell signaling. Importantly, we offer an open-source Python implementation and a GUI to facilitate SPINNA's widespread use in the scientific community.

Urothelial carcinoma is three to four times more common in men than in women, with a 73-year old mean age at diagnosis which is older than the average age at diagnosis of all cancers. Urothelial carcinoma is rare in people under 40 years of age. Smoking, exposure to industrial chemicals, and family history influence the development of bladder cancer, but age remains one of the most important risk factors. It is well established that women are more likely to be diagnosed with an advanced disease, impacting the prognosis and a higher stage-for-stage mortality compared to men. A gender difference is also observed when considering molecular features; for example, there a higher male/female ratio in Fibroblast Growth Factor Receptor 3 (FGFR3)-mutated bladder cancer. Epidermal Growth Factor Receptor (EGFR) amplifications, which are roughly depicted in 25-50% of urothelial carcinoma, have been correlated with a worse prognosis. Genomic alterations of clinical interest are mainly Human Epidermal Growth Factor Receptor 2 mutations and amplifications, as well as FGFR 3 alterations; however, no EGFR mutation has been routinely reported despite the frequency of its amplifications. Recurrently, no targeted inhibitors have demonstrated a benefit compared to platinum-based chemotherapy. We report a rare case of a 35-year-old woman presenting bone, hepatic, and lymph node metastatic urothelial carcinoma, harboring a deletion of 24 nucleotides in exon 19 of the EGFR gene with a 5-month response to osimertinib, a third-generation EGFR tyrosine kinase inhibitor.

Antibody-drug conjugates (ADCs) represent a novel class of biopharmaceuticals comprising monoclonal antibodies covalently conjugated to cytotoxic agents via engineered chemical linkers. This combination enables targeted delivery of cytotoxic agents to tumor site through recognizing target antigens by antibody while minimizing off-target effects on healthy tissues. Clinically, ADCs overcome the limitations of traditional chemotherapy, which lacks target specificity, and enhance the therapeutic efficacy of monoclonal antibodies, providing higher efficacy and fewer toxicity anti-tumor biopharmaceuticals. ADCs have ushered in a new era of targeted cancer therapy, with 15 drugs currently approved for clinical use. Additionally, ADCs are being investigated as potential therapeutic candidates for autoimmune diseases, persistent bacterial infections, and other challenging indications. Despite their therapeutic benefits, the development and application of ADCs face significant challenges, including antibody immunogenicity, linker instability, and inadequate control over the release of cytotoxic agent. How can ADCs be designed to be safer and more efficient? What is the future development direction of ADCs? This review provides a comprehensive overview of ADCs, summarizing the structural and functional characteristics of the three core components, antibody, linker, and payload. Furthermore, we systematically assess the advancements and challenges associated with the 15 approved ADCs in cancer therapy, while also exploring the future directions and ongoing challenges. We hope that this work will provide valuable insights into the design and optimization of next-generation ADCs for wider clinical applications.

Protein phosphorylation and dephosphorylation are key mechanisms that regulate cellular activities. The addition or removal of phosphate groups by specific enzymes, known as kinases and phosphatases, activates or inhibits many enzymes and receptors involved in various cell signaling pathways. Dysregulated activity of these enzymes is associated with various diseases, predominantly cancers. Synthetic and natural single- and multiple-kinase inhibitors are currently being used as targeted therapies for different tumors, including glioblastoma. Glioblastoma IDH-wild-type is the most aggressive brain tumor in adults, with a median overall survival of 15 months. The great majority of glioblastoma patients present mutations in receptor tyrosine kinase (RTK) signaling pathways responsible for tumor initiation and/or progression. Despite this, the multi-kinase inhibitor regorafenib has only recently been approved for glioblastoma patients in some countries. In this review, we analyze the history of kinase inhibitor drugs in glioblastoma therapy.

Targeted therapy with an allosteric inhibitor (AIs) is an important area of research in patients with epidermal growth factor receptor (EGFR) mutations. Current treatment of nonsmall cell lung cancer patients with EGFR mutations using orthosteric inhibitors faces challenges like resistance and stopping over phosphorylation. Notably AIs have been introduced to overcome this resistance and increase inhibitory potency that binds to pockets other than the ATP-binding site (orthosteric site). Recently, fourth-generation AIs, EAI045, have been discovered to potently and selectively inhibit various EGFR mutations but limited antiproliferative effects in the absence of the antibody cetuximab. The purpose of this work is to identify nontoxic, potent small AIs through various screening pipelines and explore their molecular mechanism. In the discovery of AIs, structural similarity search, high-throughput virtual screening, and machine learning-guided QSAR modeling, several candidates were identified. Machine learning was employed to guide the QSAR model based on 2D descriptors and DFT-derived quantum chemical descriptors followed by a PCA reduction technique, which enabled the prediction of the biological activity (IC50) of screened drugs against various EGFR mutations such as T790M/L858R/C797S and T790M/L858R. In addition, multinanosecond (ns) and microsecond (μs) classical molecular dynamics (MD) simulations run on protein-ligand binding complex to check the stability of binding dynamics for T790M/L858R/C797S and T790M/L858R mutations with lower IC50 and higher docking score compounds. The molecular mechanics generalized Boltzmann surface area (MM/GBSA) calculation revealed that the five hit allosteric molecules for T790M/C797S/L858R and two for T790M/L858R mutations had a high binding affinity. The results were corroborated further by MM/GBSA employing the normal-mode analysis entropy method to perform additional screening. Furthermore, the compounds' efficacy was confirmed using path-dependent ligand unbinding free energy techniques such as Jarzynski averaged free energy profiles obtained from adaptive steered MD, relative residence time, and umbrella sampling simulations, which were compared to a reference inhibitor. However, path-independent alchemical approaches like streamlined alchemical free energy perturbation and binding free energy estimator 2 (BFEE2) were employed to validate the results and identify potent compounds. These findings pave the way to identification of novel potential fourth-generation AIs, which require further experimental validation.

Curcumin, as a natural polyphenolic compound, possesses antitumor, antioxidant properties and anti-inflammatory. Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, and there is a lack of molecular mechanisms and therapeutic options regarding relevant therapeutic agents. Therefore, we investigated the mechanism of curcumin inhibiting pancreatic cancer growth by modulating proliferation of cells and cellular metabolism.

Bioinformatics analysis was involved in analyzing the intersecting targets of curcumin and pancreatic ductal adenocarcinoma. The effect of curcumin on proliferation of PANC-1 cells was tested by CCK-8, and total RNA from PANC-1 was also analysed by transcriptome sequencing. Molecular docking was involved in verifying binding stability of curcumin to protein targets. Molecular dynamics simulated and evaluated binding free energy, hydrogen bonds and root mean square fluctuation of the complex.

PPI, GO and KEGG were involved in screening and analysing key interacting protein targets. 40 μg/mL curcumin significantly inhibited the growth and proliferation of PANC-1. Transcriptome sequencing results showed gene expression of Cyclin D1 (CCND1), AKT serine/threonine kinase 1 (AKT1), HRas proto-oncogene (HRAS), epidermal growth factor receptor (EGFR) was significantly down-regulated by curcumin treatment. Result of molecular dynamics and molecular docking inhibited the free binding energies of CCND1/Curcumin, HRAS/Curcumin, AKT1/Curcumin and EGFR/Curcumin were -21.13 ± 3.41 kcal/mol, -21.84 ± 4.38 kcal/mol, -20.61 ± 1.82 kcal/mol and -27.37 ± 1.94 kcal/mol, respectively.

We found curcumin may not only regulate cell cycle progression in PDAC and apoptosis by down-regulating HRAS, thereby inhibiting CCND1 and its downstream signaling pathways, but also inhibit energy metabolism reprogramming, Ras-RAF-MEK-ERK and other downstream signalling pathways by down-regulating EGFR and AKT1, thereby affecting tumor cell metastasis, survival and proliferation.

Integrins are well-characterized receptors involved in cell adhesion and signaling. With six approved drugs, they are recognized as valuable therapeutic targets. Here, we explore potential activation mechanisms that may clarify the agonist versus antagonist behavior of integrin ligands. The reorganization of the transmembrane domain (TMD) in the integrin receptor, forming homooligomers within focal adhesions, could be key to the understanding of the agonistic properties of integrin ligands at substoichiometric concentrations. This has significant implications for medical applications. While we focus on the RGD peptide-recognizing integrin subfamily, we propose that these mechanistic insights may also apply to other integrin subtypes. For application of integrin ligands in medicine it is essential to consider this mechanism and its consequences for affinity and bioavailability.

Breast cancer remains the most prevalent malignancy among women globally and ranks as the leading cause of cancer-related mortality in this demographic. Approximately 13 %-15 % of all breast cancer cases are classified as HER2-positive, a subtype associated with a particularly unfavorable prognosis. A large number of patients with HER2-positive breast cancer continue to face disease progression after receiving standardized treatment. Given these challenges, a thorough exploration into the mechanisms underlying drug resistance in HER2-targeted therapy is imperative. This review focuses on the factors related to drug resistance in HER2-targeted therapy, including tumor heterogeneity, antibody-binding efficacy, variations in the tumor microenvironment, and abnormalities in signal activation and transmission. Additionally, corresponding strategies to counteract these resistance mechanisms are discussed, to advance therapeutic efficacy and clinical benefits in the management of HER2-positive breast cancer.

Introduction Epidermal growth factor receptor (EGFR) mutation analysis has become an important part of the initial workup of non-squamous non-small cell lung cancer (NS-NSCLC) patients as it is now recognized both as a prognostic and predictive marker for therapy with EGFR tyrosine kinase inhibitors (TKIs). The data on the prevalence of mutation and its clinical profile in bronchogenic adenocarcinoma are vastly available from Eastern Asian and European countries. The frequency of EGFR mutations in India however remains sparsely explored. Activating EGFR mutations in the tyrosine kinase region have been shown to underlie response to these inhibitors. However, the frequency of EGFR mutations and their clinical response in most other ethnic populations, including India, remains to be explored. In addition to providing information on the stage of the disease and the Eastern Cooperative Oncology Group (ECOG) performance scale at presentation, this is one of the rare studies from the subcontinent where EGFR mutation was performed in a single laboratory using a standardized procedure. The aims and objectives of the study are to estimate the prevalence of EGFR gene mutation in adenocarcinoma of the lung and to assess the clinical profile that correlates with EGFR gene status. Material and methods This single-center-based cross-sectional study was conducted at R.L. Jalappa Hospital, Kolar, India, over eight months (October 2023 to June 2024). The study included patients diagnosed with NSCLC adenocarcinoma whose participation was secured through informed consent. These tissues had been tested for EGFR mutational status. EGFR mutation analysis will be done on extracted DNA with real-time polymerase chain reaction to estimate the prevalence of EGFR mutation in adenocarcinoma of the lung. All data were entered in a Microsoft Excel sheet (Redmond, WA, USA) and statistical analysis will be performed using SPSS statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY). Categorical data were represented in the form of frequencies and proportions. To check the association between qualitative data, Chi-square was applied with a level of significance defined as a p-value < 0.05. Continuous data was represented as mean and standard deviation. Results Of the 61 patients included in the study, the mean age of prevalence of EGFR mutation in adenocarcinoma was 58.13 years, with a prevalence rate of 31.1%. EGFR mutation was positive in 11 (42.3%) females and eight (22.8%) males. The prevalence of exon 19 deletion was the most common and was higher in females (seven (26.4%)) compared to males (eight (22.9%)). However, among those with an ECOG score of 3, one (2.3%) had EXON 18 G719S G719A G719C, and 14 (31.8%) had EXON 19 deletion. There was a significant difference (p-value<0.008) in the type of mutations concerning the ECOG performance scale. Conclusion The prevalence of activating EGFR mutations and their clinical correlations in our study are comparable with those previously published and Indian patients with EGFR mutations. In line with data already available from previously published studies, EGFR mutation is also a common finding in patients with lung adenocarcinoma, especially among women, and the exon 19 deletion is the most common variation. Incorporating EGFR mutation testing into early diagnostic protocols remains crucial for optimizing treatment strategies and improving patient outcomes.

Glioblastoma is the most common primary brain tumor in adult patients, and despite standard-of-care treatment, median survival has remained less than two years. Advances in our understanding of molecular mutations have led to changes in the diagnostic criteria of glioblastoma, with the WHO classification integrating important mutations into the grading system in 2021. We sought to review the basics of the important genetic mutations associated with glioblastoma, including known mechanisms and roles in disease pathogenesis/treatment. We also examined new advances in image processing as well as less invasive and noninvasive diagnostic tools that can aid in the diagnosis and surveillance of those undergoing treatment for glioblastoma. Our review is intended to serve as an overview of the current state-of-the-art in the diagnosis and management of glioblastoma.

Epidermal growth factor (EGF) has important effects in the renal collecting duct to regulate salt and water transport. To identify elements of EGF-mediated signaling in the rat renal inner medullary collecting duct (IMCD), we carried out phosphoproteomic analysis. Biochemically isolated rat IMCD suspensions were treated with 1 µM of EGF or vehicle for 30 min. We performed comprehensive quantitative phosphoproteomics using tandem mass tag (TMT)-labeling of tryptic peptides followed by protein mass spectrometry. We present a data resource reporting all detected phosphorylation sites and their changes in response to EGF. For a total of 29,881 unique phosphorylation sites, 135 sites were increased and 119 sites were decreased based on stringent statistical analysis. The data are provided to users at https://esbl.nhlbi.nih.gov/Databases/EGF-phospho/. The analysis demonstrated that EGF signals through canonical EGF pathways in the renal IMCD. Analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in which EGF-regulated phosphoproteins are over-represented in native rat IMCD cells confirmed mapping to RAF-MEK-extracellular signal-regulated kinase (ERK) signaling but also pointed to a role for EGF in the regulation of protein translation. A large number of phosphoproteins regulated by EGF contained PDZ domains that are key elements of epithelial polarity determination. We also provide a collecting duct EGF-network map as a user-accessible web resource at https://esbl.nhlbi.nih.gov/Databases/EGF-network/. Overall, the phosphoproteomic data presented provide a useful resource for experimental design and modeling of signaling in the renal collecting duct.NEW & NOTEWORTHY EGF negatively regulates transepithelial water and salt transport across the kidney collecting duct. This study identified phosphoproteins affected by EGF stimulation in normal rat collecting ducts, providing insights into global cell signaling mechanisms. Bioinformatic analyses highlighted enhanced canonical ERK signaling alongside a diminished activity in the PI3K-Akt pathway, which is crucial for cell proliferation and survival. This EGF response differs somewhat from prior studies where both pathways were prominently activated.

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play a crucial role in glioblastoma (GBM) progression by interacting with glioma stem cells (GSCs). These interactions lead to the polarization of TAMs toward an M2 phenotype, which, in turn, enhances the stem-like traits and malignant progression of GSCs. Our study shows that FSTL1, a protein released by GSCs, is significantly elevated in gliomas and linked to the progression of the disease. By suppressing FSTL1 in a mouse model, we observed reduced tumor growth and a decrease in M2 macrophages. In vitro studies show that FSTL1 from GSCs promotes M2 polarization and infiltration. Importantly, GSCs utilize autocrine FSTL1 to interact with TLR2, which inhibits the endocytosis-lysosomal degradation pathway mediated by EGFR, resulting in the activation of the PI3K-AKT signaling pathway that is critical for maintaining their self-renewal. These findings underscore the importance of FSTL1 in GSC maintenance and M2 macrophage polarization, suggesting that interventions targeting the FSTL1/TLR2 pathway could provide a novel therapeutic approach for GBM patients.

ADAM17 is a member of the disintegrin and metalloproteinase (ADAM) family of transmembrane proteases with immunoregulatory activity in multiple signaling pathways. The functional ADAM17 is involved in the shedding of the ectodomain characterizing many substrates belonging to growth factors, cytokines, receptors, and adhesion molecules. The ADAM17-dependent pathways are known to be crucial in tumor development and progression and in the modulation of many pathological and physiological processes. In the last decade, ADAM17 was considered the driver of several autoimmune pathologies, and numerous substrate-mediated signal transduction pathways were identified. However, the discoveries made to date have led researchers to try to clarify the multiple mechanisms in which ADAM17 is involved and to identify any molecular gaps between the different transductional cascades. In this review, we summarize the most recent updates on the multiple regulatory activities of ADAM17, focusing on reported data in the field of autoimmunity.

Biochemical interactions at membranes are the starting points for cell signaling networks. But bimolecular reaction kinetics are difficult to experimentally measure on 2-dimensional membranes and are usually measured in volumetric in vitro assays. Membrane tethering produces confinement and steric effects that will significantly impact binding rates in ways that are not readily estimated from volumetric measurements. Also, there are situations when 2D reactions do not conform to simple kinetics. Here we show how highly coarse-grained molecular simulations using the SpringSaLaD software can be used to estimate membrane- tethered rate constants from experimentally determined volumetric kinetics. The approach is validated using an analytical solution for dimerization of binding sites anchored via stiff linkers. This approach can provide 2-dimensional bimolecular rate constants to parameterize cell-scale models of receptor-mediated signaling. We explore how factors such as molecular reach, steric effects, disordered domains, local concentration and diffusion affect the kinetics of binding. We find that for reaction-limited cases, the key determinant in converting 3D to 2D rate constant is the distance of the binding sites from the membrane. On the other hand, the mass action rate law may no longer be obeyed for diffusion-limited reaction on surfaces; the simulations reveal when this situation pertains. We then apply our approach to epidermal growth factor receptor (EGFR) mediated activation of the membrane-bound small GTPase Ras. The analysis reveals how prior binding of Ras to the allosteric site of SOS, a guanine nucleotide exchange factor (GEF) that is recruited to EGFR, significantly accelerates its catalytic activity.

The enteric nervous system (ENS) in the wall of the gastrointestinal tract is complex and comprises many neurons, which are differentiated in terms of structure, function and neurochemistry. Neuregulin 1 (NRG 1) is one of the neuronal factors synthesised in the ENS about the distribution and functions of which relatively little is known. The present study is the first description of the distribution of NRG 1 in the ENS in various segments of the porcine small intestine.

Fragments were excised from the duodenum, jejunum and ileum of five euthanised Piétrain × Duroc sows, 18-20 kg in weight and eight weeks of age. Paraformaldehyde-fixed and dehydrated tissue was sectioned and double-labelling immunofluorescence was performed using Alexa Fluor-conjugated secondary antibodies to visualise neuregulin 1 and its colocalisation with vasoactive intestinal polypeptide (VIP), galanin (GAL), and the neuronal isoform of nitric oxide synthase (nNOS) in the myenteric and inner and outer submucosal plexuses, with PGP 9.5 serving as a pan-neuronal marker.

Neuregulin 1 was observed in all enteric plexuses in each segment of the small intestine. The percentage of NRG 1-positive neurons ranged from 8.38 ± 0.55% of all neurons in the jejunal inner submucous plexus to 21.52 ± 0.98% in the duodenal myenteric plexus. Cells which were NRG 1-positive also contained VIP, GAL and nNOS in all segments of the small intestine to a degree which varied by small intestine segment and enteric plexus type.

The results indicate that NRG 1-positive neurons are present in the ENS of the porcine small intestine and differ significantly neurochemically, which may suggest a multifaceted role for NRG-1 in the controlling of the small intestine activity.

Acinetobacter baumannii (A. baumannii) has long been recognized primarily as a hospital-acquired pathogen. However, recent studies have uncovered a potential link between this bacterium and oral cancer, necessitating a deeper exploration of this relationship. This review examines the relevance of A. baumannii biofilms in the context of oral cancer development. By synthesizing current knowledge, we seek to provide a comprehensive understanding of this emerging area of research and identify critical directions for future investigations. The review emphasizes the remarkable adaptability, environmental resilience, and antibiotic resistance of A. baumannii, delves into the molecular mechanisms of biofilm formation, and their potential connection to oral cancer progression. The review also evaluates how biofilm colonization on oral surfaces and medical devices, along with its role in chronic infections, inflammation, and increased antimicrobial resistance, could contribute to creating a microenvironment favourable for tumor development. This review underscores the broader healthcare implications of A. baumannii biofilms, evaluates current strategies for their prevention and eradication, and calls for interdisciplinary research in this emerging field. By shedding light on the complex interactions between A. baumannii biofilms and oral cancer, it aims to stimulate further research and guide the development of new diagnostic, preventive, and therapeutic strategies in both microbiology and oncology.

Head and neck cancers (HNC) are aggressive, difficult-to-treat tumors that can be caused by genetic factors but mainly by lifestyle or infection caused by the human papillomavirus. As the sixth most common malignancy, it presents a formidable therapeutic challenge with limited therapeutic modalities. Curcumin, a natural polyphenol, is appearing as a promising multitarget anticancer and antimetastatic agent. Numerous studies have shown that curcumin and its derivatives have the potential to affect signaling pathways (NF-κB, JAK/STAT, and EGFR) and molecular mechanisms that are crucial for the growth and migration of head and neck tumors. Furthermore, its ability to interact with the tumor microenvironment and trigger the immune system may significantly influence the organism's immune response to the tumor. Combining curcumin with conventional therapies such as chemotherapy or radiotherapy may improve the efficacy of treatment and reduce the side effects of treatment, thereby increasing its therapeutic potential. This review is a comprehensive overview that discusses both the benefits and limitations of curcumin and its therapeutic effects in the context of tumor biology, with an emphasis on molecular mechanisms in the context of HNC. This review also includes possibilities to improve the limiting properties of curcumin both in terms of the development of new derivatives, formulations, or combinations with conventional therapies that have potential as a new type of therapy for the treatment of HNC and subsequent use in clinical practice.

The epidermal growth factor receptor 1 (EGFR) plays a crucial role in the progression of various malignant tumors and is considered a potential target for treating triple-negative breast cancer (TNBC). However, the effectiveness of representative tyrosine kinase inhibitors (TKIs) used in EGFR-targeted therapy is limited in TNBC patients. In our study, we observed that the TNBC cell lines MDA-MB-231 and MDA-MB-468 exhibited resistance to Gefitinib. Treatment with Gefitinib caused an upregulation of Fascin-1 (FSCN1) protein expression and a downregulation of miR-221-3p in these cell lines. However, sensitivity to Gefitinib was significantly improved in both cell lines with either inhibition of FSCN1 expression or overexpression of miR-221-3p. Our luciferase reporter assay confirmed that FSCN1 is a target of miR-221-3p. Moreover, Gefitinib treatment resulted in an upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in MDA-MB-231 cells. Using Stattic, a small-molecule inhibitor of STAT3, we observed a significant enhancement in the inhibitory effect of Gefitinib on the growth, migration, and invasion of MDA-MB-231 cells. Additionally, Stattic treatment upregulated miR-221-3p expression and downregulated FSCN1 mRNA and protein expression. A strong positive correlation was noted between the expression of STAT3 and FSCN1 in breast cancer tissues. Furthermore, patients with high expression levels of both STAT3 and FSCN1 had a worse prognosis. Our findings suggest that elevated FSCN1 expression is linked to primary resistance to EGFR TKIs in TNBC. Moreover, we propose that STAT3 regulates the expression of miR-221-3p/FSCN1 and therefore modulates resistance to EGFR TKI therapy in TNBC. Combining EGFR TKI therapy with inhibition of FSCN1 or STAT3 may offer a promising new therapeutic option for TNBC.

Transactivation of epidermal growth factor receptors (EGFR) provides intricate control over multiple regulatory cellular processes that merge the diversity of G protein-coupled receptors (GPCRs) with the robust signaling capacities of receptor tyrosine kinases. Contrary to the typical assertions, our findings demonstrate that EGFR transactivation contributes to the desensitization of GPCRs. Repeated agonist stimulation of certain GPCRs enhanced EGFR transactivation, triggering a series of cellular events associated with GPCR desensitization. This effect was observed in receptors undergoing desensitization (D3R, K149C-D2R, β2AR) but not in those resistant to desensitization (D2R, C147K-D3R, D4R, β2AR mutants lacking GRK2 or GRK6 phosphorylation sites). The EGFR inhibitor AG1478 prevented both desensitization and the associated cellular events. Similarly, these cellular events were also observed when cells were treated with EGF, but only in GPCRs that undergo desensitization. These findings suggest that EGFR transactivation diversifies pathways involved in ERK activation through the EGFR signaling system and also mediates GPCR desensitization. Alongside the widely accepted steric hindrance model, these findings offer new insights into understanding the mechanisms of GPCR desensitization, which occurs through complex cellular processes.

Osimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is the preferred first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) compared to first-generation EGFR-TKIs. However, limited research has compared its clinical effectiveness with second-generation (2nd G) EGFR-TKIs.

This study recruited patients diagnosed with stage IIIb-IV EGFR-mutated NSCLC who received first-line treatment with either 2nd G EGFR-TKIs (afatinib and dacomitinib) or osimertinib between April 2020 and April 2023.

The final analysis included 168 patients, of whom 113 received 2nd G EGFR-TKIs (afatinib or dacomitinib) and 55 received osimertinib. The median progression-free survival (PFS) did not differ significantly between 2nd G EGFR-TKIs and osimertinib (del 19: 17.6 months; L858R: 20.0 months vs. 28.3 months, p = 0.081). In patients with the EGFR exon 19 deletion, osimertinib conferred a longer median PFS (28.3 vs. 17.6 months, p = 0.118) and time to treatment failure (30.2 vs. 22.7 months, p = 0.722) than 2nd G EGFR-TKIs. However, the differences were not statistically significant. In patients with with the EGFR exon 19 deletion and central nervous system metastasis, the median PFS did not differ significantly between those treated with osimertinib (14.3 months) and those treated with 2nd G EGFR-TKIs (17.6 months; p = 0.881). Multivariate regression analysis revealed that the NSCLC stage was the only independent negative predictor of PFS. The treatment patterns in the second line also differed significantly between groups (p = 0.008).

This study found comparable effectiveness between osimertinib and 2nd G EGFR-TKIs as first-line treatment for advanced EGFR-mutated NSCLC, with only the NSCLC stage identified as a negative predictor of PFS. However, whether the different second-line treatments affect overall survival should be examined.

Papillary thyroid carcinoma (PTC) involves complex genetic mechanisms, notably involving CLDN1 and EGFR. This study investigates the expression and variations of these genes and their effects on tumor behavior and patient outcomes. Meta-analysis of CLDN1 and EGFR expression in TCGA-PTC patients and GEO datasets was conducted. cBioPortal was used for clinical analysis. GSEA, GO, KEGG, Hallmark pathways, and cibersort analysis were applied. Cell proliferation, migration, invasion, and apoptosis were assessed in vitro. Co-culturing with CD8+ T cells, MTT assay, ELISA, subcutaneous tumor models, and immunohistochemistry were performed. TGF-β pathway-related proteins were analyzed via Western blot. CLDN1 and EGFR were overexpressed in PTC tumors, correlating with higher-risk patients and reduced CD8+ T cell infiltration. Silencing these genes inhibited tumor cell functions and enhanced CD8+ T cell activity, both in vitro and in vivo. CLDN1 and EGFR are crucial in PTC, linked to tumor invasiveness, EMT, and immune suppression, presenting them as potential therapeutic targets.

Liver fibrosis is a pathological process caused by a variety of chronic liver diseases. Currently, therapeutic options for liver fibrosis are very limited, highlighting the urgent need to explore new treatment approaches. Epigenetic modifications and epitranscriptomic modifications, as reversible regulatory mechanisms, are involved in the development of liver fibrosis. In recent years, researches in epitranscriptomics and epigenetics have opened new perspectives for understanding the pathogenesis of liver fibrosis. Exploring the epigenetic mechanisms of liver fibrosis may provide valuable insights into the development of new therapies for chronic liver diseases. This review primarily focus on the regulatory mechanisms of N6-methyladenosine (m6A) modification, non-coding RNA, and DNA methylation in organ fibrosis. It discusses the interactions between m6A modification and DNA methylation, as well as between m6A modification and non-coding RNA, providing a reference for understanding the interplay between epitranscriptomics and epigenetics.

The extracellular environment is sensed by receptors in the plasma membrane. Some of these receptors initiate cytoplasmic signaling cascades involving phosphorylation: the addition of a phosphate group to a specific amino acid, such as tyrosine, in a protein. Receptor Tyrosine Kinases (RTKs) are one large class of membrane receptors that can directly initiate signaling cascades through their intracellular kinase domains, which both catalyze tyrosine phosphorylation and get phosphorylated. In the first step of signaling, the ligands stabilize phosphorylation-competent RTK dimers and oligomers, which leads to the phosphorylation of specific tyrosine residues in the activation loop of the kinases. Here we discuss quantitative measurements of tyrosine phosphorylation efficiencies for RTKs, described by the "transducer function". The transducer function links the phosphorylation (the response) and the binding of the activating ligand to the receptor (the stimulus). We overview a methodology that allows such measurements in direct response to ligand binding. We discuss experiments which demonstrate that EGF is a partial agonist, and that two tyrosines in the intracellular domain of EGFR, Y1068 and Y1173, are differentially phosphorylated in the EGF-bound EGFR dimers.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Metastatic breast cancer (mBC) poses a significant threat to women's health and is a major cause of malignant neoplasms in women. Human epidermal growth factor receptor (HER)3, an integral member of the ErbB/HER receptor tyrosine kinase family, is a crucial activator of the phosphoinositide-3 kinase/protein kinase B signaling pathway. HER3 overexpression significantly contributes to the development of resistance to drugs targeting other HER receptors, such as HER2 and epidermal growth factor receptors, and plays a crucial role in the onset and progression of mBC. Recently, numerous HER3-targeted therapeutic agents, such as monoclonal antibodies (mAbs), bispecific antibodies (bAbs), and antibody-drug conjugates (ADCs), have emerged. However, the efficacy of HER3-targeted mAbs and bAbs is limited when used individually, and their combination may result in toxic adverse effects. On the other hand, ADCs are cytotoxic to cancer cells and can bind to target cells through antibodies, which highlights their use in targeted HER3 therapy for mBC. This review provides an overview of recent advancements in HER3 research, historical initiatives, and innovative approaches in targeted HER3 therapy for metastatic breast cancer. Evaluating the advantages and disadvantages of current methods may yield valuable insights and lessons.

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

The widespread application of organophosphate flame retardants has led to pervasive exposure to organophosphate esters (OPEs), prompting considerable concerns regarding their potential health risk to humans. Despite hints from previous research about OPEs' association with breast cancer, their specific effects and underlying mechanisms of triple-negative breast cancer (TNBC) remain unclear. In this study, we investigated the effects of four representative OPEs on cell proliferation, cell cycle regulation, migration, and the expression of genes and proteins associated with the epidermal growth factor receptor (EGFR) and Hippo signaling pathways in TNBC (MDA-MB-231) cells. Our findings revealed that treatment with 1-25 μM triphenyl phosphate (TPHP) and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) induced TNBC cell proliferation and accelerated cell cycle progression, with upregulation in MYC, CCND1, and BRCA1 mRNA. Moreover, exposure to 1-25 μM TPHP, 10-25 μM TDCIPP, and 1-10 μM tris (2-chloroethyl) phosphate (TCEP) induced MMP2/9 mRNA expression and enhanced migratory capacity, except for 2-ethylhexyl diphenyl phosphate (EHDPP). Mechanistically, four OPEs treatments activated the EGFR-ERK1/2 and EGFR-PI3K/AKT signaling pathways by increasing the transcript of EGFR, ERK1/2, PI3K, and AKT mRNA. OPEs treatment also suppressed the Hippo signaling pathway by inhibiting the expression of MST1 mRNA and phosphorylation of LATS1, leading to the overactivation of YAP1 protein, thereby promoting TNBC cell proliferation and migration. In summary, our study elucidated that activation of the EGFR signaling pathway and suppression of the Hippo signaling pathway contributed to the proliferation, cell cycle dysregulation, and migration of TNBC cells following exposure to OPEs.

Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other's efficacy, paving the way for promising future therapeutic advancements.

The inflamed mucosa contains a complex assortment of proteases that may participate in wound healing or the development of inflammation-associated colon cancer. We sought to determine the role of protease-activated receptor 2 (PAR2) in epithelial wound healing in both untransformed and transformed colonic epithelial cells. Monolayers of primary epithelial cells derived from organoids cultivated from patient colonic biopsies and of the T84 colon cancer cell line were grown to confluence, wounded in the presence of a selective PAR2-activating peptide, and healing was visualized by live cell microscopy. Inhibitors of various signaling molecules were used to assess the relevant pathways responsible for wound healing. Activation of PAR2 induced an enhanced wound-healing response in T84 cells but not primary cells. The PAR2-enhanced wound-healing response was associated with the development of lamellipodia in cells at the wound edge, consistent with sheet migration. The response to PAR2 activation in T84 cells was completely dependent on Src kinase activity and partially dependent on Rac1 activity. The Src-associated signaling molecules, focal adhesion kinase, and epidermal growth factor receptor, which typically mediate wound-healing responses, were not involved in the PAR2 response. Experiments repeated in the presence of the inflammatory cytokines TNF and IFNγ revealed a synergistically enhanced PAR2 wound-healing response in T84s but not primary cells. The epithelial response to proteases may be different between primary and cancer cells and is accentuated in the presence of inflammatory cytokines. Our findings have implications for understanding epithelial restitution in the context of inflammatory bowel disease (IBD) and inflammation-associated colon cancer.NEW & NOTEWORTHY Protease-activated receptor 2 enhances wound healing in the T84 colon cancer cell line, but not in primary cells derived from patient biopsies, an effect that is synergistically enhanced in the presence of the inflammatory cytokines TNF and IFNγ.

Prostate cancer is the most common non-cutaneous cancer among men in the UK, causing significant health and economic burdens. Diagnosis and risk prognostication can be challenging due to the genetic and clinical heterogeneity of prostate cancer as well as uncertainties in our knowledge of the underlying biology and natural history of disease development. Urinary extracellular vesicles (EVs) are microscopic, lipid bilayer defined particles released by cells that carry a variety of molecular cargoes including nucleic acids, proteins and other molecules. Urine is a plentiful source of prostate-derived EVs. In this narrative review, we summarise the evidence on the function of urinary EVs and their applications in the evolving field of prostate cancer diagnostics and active surveillance. EVs are implicated in the development of all hallmarks of prostate cancer, and this knowledge has been applied to the development of multiple diagnostic tests, which are largely based on RNA and miRNA. Common gene probes included in multi-probe tests include PCA3 and ERG, and the miRNAs miR-21 and miR-141. The next decade will likely bring further improvements in the diagnostic accuracy of biomarkers as well as insights into molecular biological mechanisms of action that can be translated into opportunities in precision uro-oncology.

There is a strong relationship between the dysregulation of epidermal growth factor receptor (EGFR) and the development of epithelial-derived cancers. Therefore, EGFR has usually been considered the desired target for gene therapy. Here, we propose an approach for targeting EGFR-expressing cells by phage particles capable of displaying EGF and GFP as tumor-targeting and reporting elements, respectively. For this purpose, the superfolder GFP-EGF (sfGFP-EGF) coding sequence was inserted at the N-terminus of the pIII gene in the pIT2 phagemid. The capability of the constructed phage to recognize EGFR-overexpressing cells was monitored by fluorescence microscopy, fluorescence-activated cell sorting (FACS), and cell-based ELISA experiments. FACS analysis showed a significant shift in the mean fluorescence intensity (MFI) of the cells treated with phage displaying sfGFP-EGF compared to phage displaying only sfGFP. The binding of phage displaying sfGFP-EGF to A-431 cells, monitored by fluorescence microscopy, indicated the formation of the sfGFP-EGF-EGFR complex on the surface of the treated cells. Cell-based ELISA experiments showed that phages displaying either EGF or sfGFP-EGF can specifically bind EGFR-expressing cells. The vector constructed in the current study has the potential to be engineered for gene delivery purposes as well as cell-based imaging for tumor detection.

Given their good antitumor effects, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-sensitive mutations, including exon 19 deletions and exon 21 L858R mutations. EGFR fusion mutations and EGFR amplification are very rare in non-small cell lung cancer (NSCLC). We describe 2 patients with NSCLC harboring EGFR fusion mutations (EGFR-MACF1 and EGFR-GNAT3) combined with EGFR amplification. Both patients received EGFR-TKI treatment, and 1 of them showed an antitumor response.

Adaptor proteins play essential roles in various intracellular signaling pathways. Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that possesses pleckstrin homology (PH) and Src homology 2 (SH2) domains, as well as a YXXQ signal transducer and activator of transcription 3 (STAT3)-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (BRK). STAP-2/BRK expression is deregulated in breast cancers and enhances STAT3-dependent cell proliferation. In prostate cancer cells, STAP-2 interacts with and stabilizes epidermal growth factor receptor (EGFR) after stimulation, resulting in the upregulation of EGFR signaling, which contributes to cancer-cell proliferation and tumor progression. Therefore, inhibition of the interaction between STAP-2 and BRK/EGFR may be a possible therapeutic strategy for these cancers. For this purpose, peptides that interfere with STAP-2/BRK/EGFR binding may have great potential. Indeed, the identified peptide inhibitor successfully suppressed the STAP-2/EGFR protein interaction, EGFR stabilization, and cancer-cell growth. Furthermore, the peptide inhibitor suppressed tumor formation in human prostate- and lung-cancer cell lines in a murine xenograft model. This review focuses on the inhibitory peptide as a promising candidate for the treatment of prostate and lung cancers.

Biocatalytic C-H oxidation reactions are of important synthetic utility, provide a sustainable route for selective synthesis of important organic molecules, and are an integral part of fundamental cell processes. The multidomain non-heme Fe(ii)/2-oxoglutarate (2OG) dependent oxygenase AspH catalyzes stereoselective (3R)-hydroxylation of aspartyl- and asparaginyl-residues. Unusually, compared to other 2OG hydroxylases, crystallography has shown that AspH lacks the carboxylate residue of the characteristic two-His-one-Asp/Glu Fe-binding triad. Instead, AspH has a water molecule that coordinates Fe(ii) in the coordination position usually occupied by the Asp/Glu carboxylate. Molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies reveal that the iron coordinating water is stabilized by hydrogen bonding with a second coordination sphere (SCS) carboxylate residue Asp721, an arrangement that helps maintain the six coordinated Fe(ii) distorted octahedral coordination geometry and enable catalysis. AspH catalysis follows a dioxygen activation-hydrogen atom transfer (HAT)-rebound hydroxylation mechanism, unusually exhibiting higher activation energy for rebound hydroxylation than for HAT, indicating that the rebound step may be rate-limiting. The HAT step, along with substrate positioning modulated by the non-covalent interactions with SCS residues (Arg688, Arg686, Lys666, Asp721, and Gln664), are essential in determining stereoselectivity, which likely proceeds with retention of configuration. The tetratricopeptide repeat (TPR) domain of AspH influences substrate binding and manifests dynamic motions during catalysis, an observation of interest with respect to other 2OG oxygenases with TPR domains. The results provide unique insights into how non-heme Fe(ii) oxygenases can effectively catalyze stereoselective hydroxylation using only two enzyme-derived Fe-ligating residues, potentially guiding enzyme engineering for stereoselective biocatalysis, thus advancing the development of non-heme Fe(ii) based biomimetic C-H oxidation catalysts, and supporting the proposal that the 2OG oxygenase superfamily may be larger than once perceived.

Breast cancer is the most common type of lethal cancer in women globally. Women have a 1 in 8 chance of developing breast cancer in their lifetime. Among the four primary molecular subtypes (luminal A, luminal B, HER2+, and triple-negative), HER2+ accounts for 20-25 % of all breast cancer and is rather aggressive. Although the treatment outcome of HER2+ breast cancer patients has been significantly improved with anti-HER2 agents, primary and acquired drug resistance present substantial clinical issues, limiting the benefits of HER2-targeted treatment. MicroRNAs (miRNAs) play a central role in regulating acquired drug resistance. miRNA are single-stranded, non-coding RNAs of around 20-25 nucleotides, known for essential roles in regulating gene expression at the post-transcriptional level. Increasing evidence has demonstrated that miRNA-mediated alteration of gene expression is associated with tumorigenesis, metastasis, and tumor response to treatment. Comprehensive knowledge of miRNAs as potential markers of drug response can help provide valuable guidance for treatment prognosis and personalized medicine for breast cancer patients.