Epidermal Growth Factor Receptor Research Articles

Transglutaminase 2 serves as a pathogenic hub gene of KRAS mutant colon cancer based on integrated analysis

BACKGROUND Colon cancer is acknowledged as one of the most common malignancies worldwide, ranking third in United States regarding incidence and mortality. Notably, approximately 40% of colon cancer cases harbor oncogenic KRAS mutations, resulting in the continuous activation of epidermal growth factor receptor signaling. AIM To investigate the key pathogenic genes in KRAS mutant colon cancer holds considerable importance. METHODS Weighted gene co-expression network analysis, in combination with additional bioinformatics analysis, were conducted to screen the key factors driving the progression of KRAS mutant colon cancer. Meanwhile, various in vitro experiments were also conducted to explore the biological function of transglutaminase 2 (TGM2). RESULTS Integrated analysis demonstrated that TGM2 acted as an independent prognostic factor for progression-free survival. Immunohistochemical analysis on tissue microarrays revealed that TGM2 was associated with an elevated probability of perineural invasion in patients with KRAS mutant colon cancer. Additionally, biological roles of the key gene TGM2 was also assessed, suggesting that the downregulation of TGM2 attenuated the proliferation, invasion, and migration of the KRAS mutant colon cancer cell line. CONCLUSION This study underscores the potential significance of TGM2 in the progression of KRAS mutant colon cancer. This insight not only offers a theoretical foundation for therapeutic approaches but also highlights the need for additional clinical trials and fundamental research to support our preliminary findings.

Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy.

Based on the close relationship between programmed death protein ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) in glioblastoma (GBM), we designed and synthesized a series of small molecules as potential dual inhibitors of EGFR and PD-L1. Among them, compound EP26 exhibited the highest inhibitory activity against EGFR (IC50 = 37.5 nM) and PD-1/PD-L1 interaction (IC50 = 1.77 μM). In addition, EP26 displayed superior in vitro antiproliferative activities and in vitro immunomodulatory effects by promoting U87MG cell death in a U87MG/Jurkat cell coculture model. Furthermore, EP26 possessed favorable pharmacokinetic properties (F = 22%) and inhibited tumor growth (TGI = 92.0%) in a GBM mouse model more effectively than Gefitinib (77.2%) and NP19 (82.8%). Moreover, EP26 increased CD4+ cells and CD8+ cells in tumor microenvironment. Collectively, these results suggest that EP26 represents the first small-molecule-based PD-L1/EGFR dual inhibitor deserving further investigation as an immunomodulating agent for cancer treatment.

Quality-adjusted life years for HER2-positive, early-stage breast cancer using trastuzumab-containing regimens in the context of cost-effectiveness studies: a systematic review.

This study aims to provide a comprehensive assessment of economic and health-related quality of life (HRQoL) outcomes for human epidermal growth factor receptor 2 (HER2)-positive, early-stage breast cancer patients treated with trastuzumab-containing regimens, by focusing on both Incremental Cost-Effectiveness Ratios (ICERs) and quality-adjusted life years (QALYs). A systematic search was conducted across PubMed, Embase, and Scopus databases without language or publication year restrictions. Two independent reviewers screened eligible studies, extracted data, and assessed methodology and reporting quality using the Drummond checklist and Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022), respectively. Costs were converted to US dollars (US$) for 2023 for cross-study comparison. Twenty-two articles, primarily from high-income countries (HICs), were included, with ICERs ranging from US$13,176/QALY to US$254,510/QALY, falling within country-specific cost-effectiveness thresholds. A notable association was observed between higher QALYs and lower ICERs, indicating a favorable cost-effectiveness and health outcome relationship. EQ-5D was the most utilized instrument for assessing health state utility values, with diverse targeted populations. Studies reporting higher QALYs tend to have lower ICERs, indicating a positive relationship between cost-effectiveness and health outcomes. However, challenges such as methodological heterogeneity and transparency in utility valuation persist, underscoring the need for standardized guidelines and collaborative efforts among stakeholders. PROSPERO ID: CRD42021259826.

Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation.

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.

CLINICAL FACTORS PREDECTING T790M MUTATION IN NON-SMALL CELL LUNG CANCER PROGRESSED AFTER FIRST- AND SECOND-GENERATION TKI TREATMENT

Objective: We aimed to identify the T790M mutation rate and clinical factors predicting the occurrence of acquired T790M mutations in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after first- and second-generation tyrosine kinase inhibitor (TKI) treatment. Method: The EGFR-mutant NSCLC patients who experienced progression after first- and second-generation TKI treatment and underwent testing for EGFR using plasma samples between January 2021 and April 2023 were enrolled. The T90M mutation rate and related clinical factors were evaluated. We utilized the Chi-square test or Fisher’s exact test for univariate analysis and multivariable logistic binary regression for multivariate analysis. Results: A total of 247 patients were eligible for the study. Patients harbored the exon 19 deletion mutation (Del19), exon 21 L858R point mutation, and uncommon mutations in 63.2%, 34.4%, and 2.4% of cases, respectively. The overall T790M mutation rate was 33.6%. In multivariate analyses, the Del19 mutation versus L858R mutation, duration of first-line TKI exceeding 12 months versus below 12 months, and solitary lesion progression versus multiple lesion progression were identified as favorable prognostic factors for the occurrence of T790M mutation. Conclusion: Patients with EGFR exon 19 deletion, a prolonged treatment duration of first-line EGFR-TKI, and solitary lesion progression pattern are more likely to acquire the T790M mutation, as detected by the PCR method in plasma samples.

Prognostic significance of HER2 loss after HER2-targeted neoadjuvant treatment in patients with HER2-positive locally advanced breast cancer

Loss of human epidermal growth factor receptor 2 (HER2) expression can be seen in almost 25–30 % patients after HER2 receptor directed neoadjuvant treatment. These patients have unclear clinical outcomes in previous studies. We aimed to investigate the importance of HER2 loss, additionally with predictive factors for the loss of HER2. This was a retrospective and multicenter study that included 272 HER2-positive BC patients with no pathological complete response who received neoadjuvant chemotherapy plus HER2-targeted treatments. The factors that may affect the loss of HER2 detected by immunohistochemistry(IHC) and the association with survival were analyzed.The rate of HER2 loss after neoadjuvant treatments(NAT) was 27.9 % (n = 76). Disease recurrence was observed in 18(23.7 %) patients with HER2 loss, while it was detected in 62 (31.7 %) patients without HER2 loss(p = 0.23). Pre and post-NAT ER status, and post-NAT ki-67 status had a significant impact on disease-free survival(DFS) (p = 0.0012, p = 0.004, and p = 0.04, respectively).There were no significant association between DFS and loss of HER2 (p = 0.64) and dual anti-HER2 blockade (p = 0.21). Pre-NAT clinical stage (HR:1.65 p = 0.013), post-NAT LN status (HR:3.18, p = 0.02) and pre-NAT ER status (HR:0.24, p = 0.041) were significant independent prognostic factors for DFS while post-NAT residual disease in axillar tissue was an independent prognostic factor for OS (HR:1.54 p = 0.019). Moreover, age (<40 years vs ≥40 years) (p = 0.031) and tumor grade (p = 0.004) were predictive factors for HER2 loss. Our results showed that HER2 loss did not affect survivals. However, young age and being high grade tumor may predict HER2 loss.

The value of dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting EGFR mutations

Objectives18F-fluorodeoxyglucose (FDG) PET/CT has been widely used for the differential diagnosis of cancer. Semi-quantitative standardized uptake value (SUV) is known to be affected by multiple factors and may make it difficult to differentiate between benign and malignant lesions. It is crucial to find reliable quantitative metabolic parameters to further support the diagnosis. This study aims to evaluate the value of the quantitative metabolic parameters derived from dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting epidermal growth factor receptor (EGFR) mutation status.MethodsWe included 147 patients with lung lesions to perform FDG PET/CT dynamic plus static imaging with informed consent. Based on the results of the postoperative pathology, the patients were divided into benign/malignant groups, adenocarcinoma (AC)/squamous carcinoma (SCC) groups, and EGFR-positive (EGFR+)/EGFR-negative (EGFR-) groups. Quantitative parameters including K1, k2, k3, and Ki of each lesion were obtained by applying the irreversible two-tissue compartmental modeling using an in-house Matlab software. The SUV analysis was performed based on conventional static scan data. Differences in each metabolic parameter among the group were analyzed. Wilcoxon rank-sum test, independent-samples T-test, and receiver-operating characteristic (ROC) analysis were performed to compare the diagnostic effects among the differentiated groups. P < 0.05 were considered statistically significant for all statistical tests.ResultsIn the malignant group (N = 124), the SUVmax, k2, k3, and Ki were higher than the benign group (N = 23), and all had-better performance in the differential diagnosis (P < 0.05, respectively). In the AC group (N = 88), the SUVmax, k3, and Ki were lower than in the SCC group, and such differences were statistically significant (P < 0.05, respectively). For ROC analysis, Ki with cut-off value of 0.0250 ml/g/min has better diagnostic specificity than SUVmax (AUC = 0.999 vs. 0.70). In AC group, 48 patients further underwent EGFR testing. In the EGFR (+) group (N = 31), the average Ki (0.0279 ± 0.0153 ml/g/min) was lower than EGFR (-) group (N = 17, 0.0405 ± 0.0199 ml/g/min), and the difference was significant (P < 0.05). However, SUVmax and k3 did not show such a difference between EGFR (+) and EGFR (-) groups (P>0.05, respectively). For ROC analysis, the Ki had a cut-off value of 0.0350 ml/g/min when predicting EGFR status, with a sensitivity of 0.710, a specificity of 0.588, and an AUC of 0.674 [0.523–0.802].ConclusionAlthough both techniques were specific, Ki had a greater specificity than SUVmax when the cut-off value was set at 0.0250 ml/g/min for the differential diagnosis of lung cancer. At a cut-off value of 0.0350 ml/g/min, there was a 0.710 sensitivity for EGFR status prediction. If EGFR testing is not available for a patient, dynamic imaging could be a valuable non-invasive screening method.

Preoperative Differentiation of HER2-Zero and HER2-Low from HER2-Positive Invasive Ductal Breast Cancers Using BI-RADS MRI Features and Machine Learning Modeling.

Accurate determination of human epidermal growth factor receptor 2 (HER2) is important for choosing optimal HER2 targeting treatment strategies. HER2-low is currently considered HER2-negative, but patients may be eligible to receive new anti-HER2 drug conjugates. To use breast MRI BI-RADS features for classifying three HER2 levels, first to distinguish HER2-zero from HER2-low/positive (Task-1), and then to distinguish HER2-low from HER2-positive (Task-2). Retrospective. 621 invasive ductal cancer, 245 HER2-zero, 191 HER2-low, and 185 HER2-positive. For Task-1, 488 cases for training and 133 for testing. For Task-2, 294 cases for training and 82 for testing. 3.0 T; 3D T1-weighted DCE, short time inversion recovery T2, and single-shot EPI DWI. Pathological information and BI-RADS features were compared. Random Forest was used to select MRI features, and then four machine learning (ML) algorithms: decision tree (DT), support vector machine (SVM), k-nearest neighbors (k-NN), and artificial neural nets (ANN), were applied to build models. Chi-square test, one-way analysis of variance, and Kruskal-Wallis test were performed. The P values <0.05 were considered statistically significant. For ML models, the generated probability was used to construct the ROC curves. Peritumoral edema, the presence of multiple lesions and non-mass enhancement (NME) showed significant differences. For distinguishing HER2-zero from non-zero (low + positive), multiple lesions, edema, margin, and tumor size were selected, and the k-NN model achieved the highest AUC of 0.86 in the training set and 0.79 in the testing set. For differentiating HER2-low from HER2-positive, multiple lesions, edema, and margin were selected, and the DT model achieved the highest AUC of 0.79 in the training set and 0.69 in the testing set. BI-RADS features read by radiologists from preoperative MRI can be analyzed using more sophisticated feature selection and ML algorithms to build models for the classification of HER2 status and identify HER2-low. Stage 2.

Vitreoretinal Traction Syndrome, Nitrituria and Human Epidermal Growth Factor Receptor Negative Might Occur in the Aromatase-Inhibitor Anastrozole Treatment

Background. Anastrozole has been approved for treatment of hormone receptor-positive advanced or metastatic breast cancer by FDA. This study was to assess Anastrozole-related adverse events (AEs) of real-world through data mining of the US Food and drug administration adverse event reporting system (FAERS). Methods. Four different disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multiitem gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of Anastrozole-associated AEs. Results. A total 25 system organ class (SOCs) and 300 significant disproportionality Preferred Terms (PTs) were found in this study. The top 5 most significant SOCs were Eye disorders, renal and urinary disorders, respiratory, thoracic and mediastinal disorders, investigations, and cardiac disorders. Unexpected significant AEs was vitreoretinal traction syndrome (ROR = 1108.22, PRR = 1103.98, IC025 = 9.51, EBGM05 = 389.98), nitrituria (ROR = 3561.82, PRR = 3557.28, IC025 = 10.38, EBGM05 = 318.83) and human epidermal growth factor receptor negative (ROR = 675.04, PRR = 674.01, IC025 = 9, EBGM05 = 204.57). Conclusion. The Unexpected significant AEs associated with anastrozole were identified in this study, warrants urgent clarification through additional prospective studies.

ABCG2 Mediates Resistance to the Dual EGFR and PI3K Inhibitor MTX-211 in Cancer Cells

MTX-211 is a first-in-class dual inhibitor of epidermal growth factor receptor (EGFR) and phosphoinositide-3 kinase (PI3K) signaling pathways with a compelling pharmaceutical profile and could enhance the effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitor therapy in colorectal tumors with KRAS mutations. However, the specific mechanisms contributing to the acquired resistance to MTX-211 in human cancers remain elusive. Here, we discovered that the overexpression of the ATP-binding cassette (ABC) drug transporter ABCG2, a prevalent mechanism associated with multidrug resistance (MDR), could diminish the effectiveness of MTX-211 in human cancer cells. We showed that the drug efflux activity of ABCG2 substantially decreased the intracellular accumulation of MTX-211 in cancer cells. As a result, the cytotoxicity and effectiveness of MTX-211 in suppressing the activation of the EGFR and PI3K pathways were significantly attenuated in cancer cells overexpressing ABCG2. Moreover, the enhancement of the MTX-211-stimulated ATPase activity of ABCG2 and the computational molecular docking analysis illustrating the binding of MTX-211 to the substrate-binding sites of ABCG2 offered a further indication for the interaction between MTX-211 and ABCG2. In summary, our findings indicate that MTX-211 acts as a substrate for ABCG2, underscoring the involvement of ABCG2 in the emergence of resistance to MTX-211. This finding carries clinical implications and merits further exploration.

Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography.

Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.

Association between pathologic complete response and biochemical indicators after neoadjuvant therapy for HER2-positive breast cancer

PurposeThis study investigated the changes in the fasting blood glucose (FBG), fasting triglyceride (FTG), and fasting total cholesterol (FTC) levels during neoadjuvant therapy (NAT) for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) and the association with pathologic complete response (pCR).MethodsRelevant data from Sichuan Cancer Hospital from June 2019 to June 2022 were collected and analyzed, and FBG, FTG, and FTC were divided into baseline, change, and process groups, which were grouped to analyze the changes after receiving NAT and the association with pCR.Results In the estrogen receptor (ER)-negative subgroup, patients with low levels of FTG in the process group were more likely to achieve pCR compared to high levels, and in the progesterone receptor (PR)-negative subgroup, patients with lower FTG compared to higher FTG after receiving NAT was more likely to achieve pCR.ConclusionsPatients with HER2-positive BC undergoing NAT develop varying degrees of abnormalities (elevated or decreased) in FBG, FTG, and FTC; moreover, the status of FTG levels during NAT may predict pCR in ER-negative or PR-negative HER2-positive BC.Early monitoring and timely intervention for FTG abnormalities may enable this subset of patients to increase the likelihood of obtaining a pCR along with management of abnormal markers.

Use of MRI Radiomics Models in Evaluating the Low HER2 Expression in Breast Cancer.

To investigate the magnetic resonance imaging (MRI) radiomics models in evaluating the human epidermal growth factor receptor 2(HER2) expression in breast cancer. <P> Materials and Methods: The MRI data of 161 patients with invasive ductal carcinoma (non-special type) of breast cancer were retrospectively collected, and the MRI radiomics models were established based on the MRI imaging features of the fat suppression T2 weighted image (T2WI) sequence, dynamic contrast-enhanced (DCE)-T1WIsequence and joint sequences. The T-test and the least absolute shrinkage and selection operator (LASSO) algorithm were used for feature dimensionality reduction and screening, respectively, and the random forest (RF) algorithm was used to construct the classification model. <P> Results: The model established by the LASSO-RF algorithm was used in the ROC curve analysis. In predicting the low expression state of HER2 in breast cancer, the radiomics models of the fat suppression T2WI sequence, DCE-T1WI sequence, and the combination of the two sequences showed better predictive efficiency. In the receiver operating characteristic (ROC) curve analysis for the verification set of low, negative, and positive HER2 expression, the area under the ROC curve (AUC) value was 0.81, 0.72, and 0.62 for the DCE-T1WI sequence model, 0.79, 0.65 and 0.77 for the T2WI sequence model, and 0.84, 0.73 and 0.66 for the joint sequence model, respectively. The joint sequence model had the highest AUC value. <P> Conclusions: The MRI radiomics models can be used to effectively predict the HER2 expression in breast cancer and provide a non-invasive and early assistant method for clinicians to formulate individualized and accurate treatment plans.

Transcriptomics coupled with proteomics reveals osimertinib-induced myocardial mitochondrial dysfunction

Osimertinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used for cancer treatment, can cause significant cardiac toxicity. However, the specific mechanism of osimertinib-induced cardiotoxicity is not fully understood. In this study, we administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs). We observed significant structural and functional damage to the hearts of these mice, along with a marked increase in cardiac injury biomarkers and accompanying ultrastructural damage to mitochondria. We integrated 4D label-free protein quantification and RNA-Seq methods to analyze the sequencing data of NRVMs under osimertinib treatment (0 and 2.5 μM). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis evidenced that differentially expressed genes (DEGs)and differentially expressed proteins (DEPs) were distinctly enriched for oxidative phosphorylation (OXPHOs). Simultaneously, osimertinib primarily affected the contents of adenosine triphosphate (ATP). Further investigations revealed that osimertinib disrupts the functions of the ATP synthase (complex V), leading to a reduction in ATP production. Taken together, our data demonstrated that osimertinib causes mitochondrial dysfunction, which in turn leads to the onset of cardiac toxicity.

Microfluidics-based EGFR mutation detection and its implication in the resource-limited clinical setting.

Management of lung cancer today obligates a mutational analysis of the epidermal growth factor receptor (EGFR) gene particularly when Tyrosine Kinase Inhibitor (TKI) therapy is being considered as part of prognostic stratification. This study evaluates the performance of automated microfluidics-based EGFR mutation detection and its significance in clinical diagnostic settings. Formalin-fixed, paraffin-embedded (FFPE) samples from NSCLC patients (n = 174) were included in a two-phase study. Phase I: Validation of the platform by comparing the results with conventional real-time PCR and next-generation sequencing (NGS) platform. Phase II: EGFR mutation detection on microfluidics-based platform as part of routine diagnostics workup. The microfluidics-based platform demonstrates 96.5% and 89.2% concordance with conventional real-time PCR and NGS, respectively. The system efficiently detects mutations across the EGFR gene with 88.23% sensitivity and 100% specificity. Out of 144 samples analysed in phase II, the platform generated valid results in 94% with mutation detected in 41% of samples. This microfluidics-based platform can detect as low as 5% mutant allele fractions from the FFPE samples. Therefore the microfluidics-based platform is a rapid, complete walkaway, with minimum tissue requirement (two sections of 5 μ thickness) and technical skill requirement. The method can detect clinically actionable EGFR mutations efficiently and can be considered a reliable diagnostic platform in resource-limited settings. From receiving samples to reporting the results this platform provides accurate data without much manual intervention. The study helped to devise an algorithm that emphasizes effective screening of the NSCLC cases for EGFR mutations with varying tumour content. Thus it helps in triaging the cases judiciously before proceeding with multigene testing.

EGF-like growth factors upregulate pentraxin 3 expression in human granulosa-lutein cells

The epidermal growth factor (EGF)-like factors, comprising amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG), play a critical role in regulating the ovulatory process. Pentraxin 3 (PTX3), an essential ovulatory protein, is necessary for maintaining extracellular matrix (ECM) stability during cumulus expansion. The aim of this study was to investigate the impact of EGF-like factors, AREG, BTC, and EREG on the expression and production of PTX3 in human granulosa-lutein (hGL) cells and the molecular mechanisms involved. Our results demonstrated that AREG, BTC, and EREG could regulate follicular function by upregulating the expression and increasing the production of PTX3 in both primary (obtained from 20 consenting patients undergoing IVF treatment) and immortalized hGL cells. The upregulation of PTX3 expression was primarily facilitated by the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling pathway, induced by these EGF-like factors. In addition, we found that the upregulation of PTX3 expression triggered by the EGF-like factors was completely reversed by either pretreatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, or knockdown of EGFR, suggesting that EGFR is crucial for activating the ERK1/2 signaling pathway in hGL cells. Overall, our findings indicate that AREG, BTC, and EREG may modulate human cumulus expansion during the periovulatory stage through the upregulation of PTX3.

Coptidis rhizoma extract alleviates oropharyngeal candidiasis by gC1qR-EGFR/ERK/c-fos axis-induced endocytosis of oral epithelial cells

Ethnopharmacological relevanceCoptidis rhizoma, first recorded in the “Shen Nong's Herbal Classic”, is one of the traditional Chinese medicine (TCM) used to treat infectious diseases, with reputed effectiveness against oropharyngeal candidiasis (OPC). Studies have demonstrated the inhibitory properties of C. rhizoma (CRE) against Candida albicans, yet there is limited information available regarding its treatment mechanism for OPC. Aim of the studyOur previous research has suggested that CRE can prevent the formation of C. albicans hyphae and their invasion of the oral mucosa, thereby exerting a therapeutic effect on OPC. Nevertheless, the precise therapeutic mechanisms remain incompletely understood. Previous studies have revealed that a receptor for globular heads of C1q (gC1qR), a crucial co-receptor of the epidermal growth factor receptor (EGFR), facilitates the EGFR-mediated internalization of C. albicans. Therefore, this study aims to investigate the potential mechanism of action of CRE and its primary component, berberine (BBR), in treating OPC by exploring their effects on the gC1qR-EGFR co-receptor. Materials and methodsTo identify the chemical components of CRE, we utilized Ultra-high performance liquid chromatography in conjunction with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MSE), revealing the presence of at least 18 distinct components. To observe the therapeutic effects of CRE on OPC at the animal level, we employed hematoxylin and eosin staining, periodic acid-Schiff staining, scanning electron microscopy, and fungal load detection. Subsequently, we evaluated the anti-inflammatory properties of CRE and its main component, BBR, in treating OPC. This was achieved through enzyme-linked immunosorbent assay (ELISA) both at the animal and cellular levels. Additionally, we assessed the ability of C. albicans to disrupt the epithelial barrier of FaDu cells by studying the protective effects of BBR on the fusion barrier using the transwell assay. To further explore the underlying mechanisms, we analyzed the effects of BBR on the gC1qR-EGFR/extracellular signal-regulated kinase/c-Fos signaling pathway at the cellular level using qRT-PCR, western blotting, and immunofluorescence. Furthermore, we validated the effects of BBR on the gC1qR-EGFR co-receptor through ELISA, qRT-PCR, and western blotting. Finally, to confirm the outcomes observed at the cellular level, we validated the impact of CRE on the gC1qR-EGFR co-receptor in vivo using qRT-PCR, western blotting, and immunofluorescence. These comprehensive methods allowed us to gain a deeper understanding of the therapeutic mechanisms of CRE and BBR in treating OPC. ResultsOur findings indicate that CRE and its primary component, BBR, effectively alleviated the symptoms of OPC by modulating the gC1qR-EGFR co-receptor. The chemical composition of CRE and BBR was accurately identified using UPLC-Q/TOF-MSE. The gC1qR-EGFR co-receptor plays a crucial role in regulating downstream signaling pathways, emerging as a potential therapeutic target for OPC treatment. Through both in vitro and in vivo experiments, we explored the therapeutic potential of CRE and BBR in OPC. Additionally, we employed overexpression and silencing techniques to confirm that BBR can indeed influence the gC1qR-EGFR co-receptor and regulate the gC1qR-EGFR/extracellular signal-regulated kinase (ERK)/c-Fos signaling pathway, leading to improved OPC outcomes. Furthermore, the significance of CRE's effect on the gC1qR-EGFR co-receptor was validated in vivo. ConclusionOur study demonstrates that CRE and its main component, BBR, can effectively alleviate OPC symptoms by targeting the gC1qR-EGFR heterodimer receptor. This discovery offers a promising new therapeutic approach for the treatment of OPC.

Prognostic significance of SIRI in patients with late-stage lung adenocarcinoma receiving EGFR-TKI treatment

ObjectiveIn this study, we examined the relationship between the Systemic Inflammatory Response Index (SIRI) and the overall prognosis of patients with late-stage lung adenocarcinoma who harbor epidermal growth factor receptor (EGFR) mutations and are undergoing first-line treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). MethodsA cohort comprising 52 patients with late-stage lung adenocarcinoma, who received treatment at Jinzhou Central Hospital between January 2018 and December 2022, were carefully selected. Patient data spanning from pre-treatment assessments through follow-up periods were meticulously collected from electronic medical records and subsequently subjected to a comprehensive retrospective analysis. The collected data was subjected to in-depth processing and analyzed using SPSS 27.0 statistical software. To determine the optimal cut-off value of the pre-treatment SIRI, a receiver operating characteristic (ROC) curve was employed. Survival analysis was performed using the Kaplan-Meier method, and both univariate and multivariate prognostic analyses were conducted using Cox regression. ResultsThe optimal SIRI cut-off value was determined to be 1.659 (with a specificity of 0.964 and sensitivity of 0.652, P = 0.000). Based on this value, patients were categorized into high and low SIRI groups. Chi-squared tests demonstrated that SIRI exhibited statistically significant correlations with patient age and smoking history (P < 0.05). Survival analysis revealed that the group with a lower SIRI had a significantly extended progression-free survival (PFS) (P < 0.001). Cox univariate analysis identified hypertension, pleural metastasis, liver metastasis, and SIRI as factors associated with PFS (P < 0.05). In the subsequent multivariate analysis, liver metastasis and SIRI ≥ 1.659 (P < 0.001) were identified as independent risk factors for patients. ConclusionPre-treatment SIRI holds predictive significance for the prognosis of patients with late-stage lung adenocarcinoma with EGFR mutations undergoing first-line treatment EGFR-TKI treatment.

Erlotinib suppresses tumorigenesis in a mouse model of colitis-associated cancer

Colitis-associated cancer (CAC) in inflammatory bowel diseases exhibits more aggressive behavior than sporadic colorectal cancer; however, the molecular mechanisms remain unclear. No definitive preventative agent against CAC is currently established in the clinical setting. We investigated the molecular mechanisms of CAC in the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and assessed the antitumor efficacy of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR). Erlotinib premixed with AIN-93 G diet at 70 or 140 parts per million (ppm) inhibited tumor multiplicity significantly by 96%, with ∼60% of the treated mice exhibiting zero polyps at 12 weeks. Bulk RNA-sequencing revealed more than a thousand significant gene alterations in the colons of AOM/DSS-treated mice, with KEGG enrichment analysis highlighting 46 signaling pathways in CAC development. Erlotinib altered several signaling pathways and rescued 40 key genes dysregulated in CAC, including those involved in the Hippo and Wnt signaling. These findings suggest that the clinically-used antitumor agent erlotinib might be repurposed for suppression of CAC, and that further studies are warranted on the crosstalk between dysregulated Wnt and EGFR signaling in the corresponding patient population.

Backbone and methyl side-chain resonance assignments of the single chain Fab fragment of trastuzumab.

Trastuzumab is a therapeutic monoclonal antibody developed to target human epidermal growth factor receptor 2 (HER2) present at higher levels in early cancers. Here we report the near complete resonance assignment of trastuzumab-scFab fragment backbone and the methyl groups of isoleucine, leucine and valine residues, as well as their stereo-assignments. The antibody fragment was produced using a single chain approach in Escherichia coli.