Epidermal Growth Factor Receptor Expression Research Articles

QSOX1 exerts anti-inflammatory effects in sepsis-induced acute lung injury: Regulation involving EGFR phosphorylation mediated M1 polarization of macrophages

Sepsis is a systemic inflammatory response caused by an infection, which can easily lead to acute lung injury. Quiescin Q6 sulfhydryl oxidase 1 (QSOX1) is a sulfhydryl oxidase involved in oxidative stress and the inflammatory response. However, there are few reports on the role of QSOX1 in sepsis-induced acute lung injury (SALI). In this study, mice model of SALI was constructed by intraperitoneal injection with lipopolysaccharide (LPS). The increased inflammatory response and lactate dehydrogenase activity in bronchoalveolar lavage fluid (BALF) indicated successful modeling. Increased QSOX1 expression was both observed in lung tissues and lung macrophages of sepsis mice accompanied by increased polarization of M1-type macrophages. To explore the role of QSOX1 in the SALI, lentivirus containing QSOX1-specific overexpression or knockdown vectors were used to change QSOX1 expression in LPS-treated RAW264.7 cells. QSOX1 suppressed LPS-induced M1 polarization and further inhibited inflammatory response in RAW264.7 cells. Interestingly, the phosphorylation of epidermal growth factor receptor (EGFR), the promoter of M1 polarization in macrophages, was found to be downregulated upon QSOX1 overexpression in RAW264.7 cells. Mechanically, the binding of QSOX1 to EGFR protein promoted EGFR ubiquitination and degradation, thereby down-regulating EGFR phosphorylation. Moreover, inhibiting EGFR expression or its phosphorylation restored the impact of QSOX1 silencing on M1 polarization and inflammation in the LPS-treated RAW264.7 cells. In summary, QSOX1 may exert anti-inflammatory effects in SALI by inhibiting EGFR phosphorylation-mediated M1 macrophage polarization. This presented a potential target for the treatment and prevention of SALI.

Huangqi-Danshen Decoction Against Renal Fibrosis in UUO Mice via TGF-β1 Induced Downstream Signaling Pathway.

Huangqi-Danshen decoction (HDD) is a Chinese medicinal herb pair with good efficacy in treating chronic kidney disease, but its mechanism needs to be clarified. To uncover the underlying mechanism of HDD antagonizing renal fibrosis through network pharmacology (NP) analysis and experimental validation. The chemical components of water extract of HDD were analyzed by combining the ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrum analysis (UHPLC-QE-MS) and HERB database. NP was used to identify core common targets of HDD components and renal fibrosis. Subsequently, male C57BL/6 mice were divided into Sham, unilateral ureteral obstruction (UUO) and UUO+HDD groups. Renal function, histopathology, Western blotting, and immunohistochemistry analyses were used to evaluate the protective effect of HDD on UUO mice. The effects of HDD on signaling pathways were validated in both UUO mice and transforming growth factor-β1 (TGF-β1)-induced HK-2 cells. By combining UHPLC-QE-MS analysis and HERB database, 25 components were screened in HDD extract. There were 270 intersection targets of the 25 components and renal fibrosis. Based on their scores in protein-protein interaction analysis and degree values in component-pathway-target triadic network, 6 core common targets of the 25 components and renal fibrosis were identified, namely phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription 3(Stat3), non-receptor tyrosine kinase Src (Src), epidermal growth factor receptor (EGFR), matrix metalloproteinase 9 (MMP9), and MMP2. HDD ameliorated renal tubular damage and collagen deposition and downregulated fibrosis-related proteins expression in UUO mice. Furthermore, HDD was demonstrated to reduce PI3K, Stat3, Src, EGFR, and MMP2 expressions, and enhance MMP9 expression in the kidney of UUO mice and in TGF-β1-induced HK-2 cells. HDD can alleviate renal fibrosis which may be related to regulating the expression of essential proteins in the epithelial-mesenchymal transition and extracellular matrix production/degradation signaling pathways.

Evaluation of Hydrazide-hydrazone and 4-thiazolidinone Derivatives of Etodolac as Potential Anticancer Agents in Leukemia Cells

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used for their anti-inflammatory and analgesic properties, have also been found to prevent cancer. (±)(R,S) Etodolac is an NSAID that belongs to the class of cyclooxygenase-2 inhibitors. Various derivatives of etodolac are synthesized to boost its anti-proliferative action and lessen its potential negative effects. In our earlier studies, some novel derivatives of etodolac exhibited stronger cytotoxic effects on prostate cell lines and had similar effects on leukemia cells in pre-screening experiments. Objective: Using the K562 leukemia cell line as a model, we sought to investigate the anti-cancer properties of a hydrazide-hydrozone derivative (SGK-205) and a 4-thiazolidinone derivative of etodolac (SGK-216). Materials and Methods: In the current investigation, SGK-205 and SGK-216 compounds were administered to K562 cells for 24 and 48 hours at concentrations of 10, 25, 50, 75 and 100 μM. Cell viability was assessed using the MTT test, and apoptosis by Annexin V-PI staining and mitochondrial membrane potential assays, together with mRNA expressions of apoptotic proteins. The levels of the proteins, HER2 and COX2, were also examined to evaluate COX2 inhibitory capacity. Results: In K562 cells, there was a definite dose-dependent response to SGK-205 and SGK-216 compounds. Results from MTT viability tests, together with mitochondrial membrane potential measurements and Annexin V-PI staining, revealed that SGK-216 and SGK-205 significantly outperformed etodolac in terms of their apoptotic and anti-proliferative activities. The concentration range of 10-20 M for both chemicals was sufficient to start biological responses. Apoptosis was also investigated through the expressions of pro- and anti-apoptotic proteins. Additionally, gene expression research demonstrated SGK-205 to be a beneficial substitute to etodolac in lowering COX-2 and human epidermal growth factor receptor-2 (HER2) expression. Conclusion: Our data indicated both derivatives to have higher anti-proliferative and apoptotic effects compared to etodolac. An overall assessment highlighting apoptotic induction potential, acceptable toxicity levels, a consistent dose-response relationship, and COX2 inhibitory actions, in particular, indicated SGK-205 as a viable novel therapeutic.

Chemo-Enzymatic Functionalization of Bovine Milk Exosomes with an EGFR Nanobody for Target-specific Drug Delivery.

Bovine milk exosomes (BmExo) have been identified as versatile nanovesicles for anti-cancer drugs delivery due to their natural availability and biocompatibility. However, tumor-specific delivery based on BmExo often requires post-isolation modifications of the membrane surface with active-targeting ligands. In this study, we report an alternative approach to functionalize BmExo with nanobody combining facile chemical modification and Sortase A-mediated site-specific ligation, as demonstrated by the development of an epidermal growth factor receptor (EGFR)-targeted drug delivery system. The BmExo membrane was first coated with a diglycine-containing amphiphile molecule, NH2-GG-PEG2000-DSPE, by hydrophobic insertion. The diglycine as nucleophiles displayed on the membrane enabled the subsequent ligation of the EGFR nanobody (7D12) by Sortase A (SrtA)-mediated site-specific transpeptidation. The successful construction of BmExo-7D12 was confirmed by Western blotting analysis, electron microscopy, and dynamic light scattering (DLS). As a demonstration model, BmExo-7D12 loaded with the chemotherapeutic drug doxorubicin (Dox) was shown to be able to deliver Dox to cancer cells in response to the expression of EGFR as manifested by immunocytochemistry and flow cytometry analysis. Finally, the cytotoxicity assay showed that BmExo-7D12-Dox was more effective in killing tumor cells with high EGFR expression while significantly reduced the non-specific toxicity to EGFR negative cells. In conclusion, these results demonstrate that 7D12-functionalized BmExo can serve as a target-specific delivery system for Dox to selectively kill EGFR-expressing tumor cells. This approach should prove to be versatile and efficient for the generation of protein-ligands modified BmExo.

Multispectral fluorescence imaging of EGFR and PD-L1 for precision detection of oral squamous cell carcinoma: a preclinical and clinical study

BackgroundEarly detection and treatment are effective methods for the management of oral squamous cell carcinoma (OSCC), which can be facilitated by the detection of tumor-specific OSCC biomarkers. The epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) are important therapeutic targets for OSCC. Multispectral fluorescence molecular imaging (FMI) can facilitate the detection of tumor multitarget expression with high sensitivity and safety. Hence, we developed Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes, in combination with multispectral FMI, to sensitively and noninvasively identify EGFR and PD-L1 expression for the detection and comprehensive treatment of OSCC.MethodsThe expression of EGFR and PD-L1 was analyzed using bioinformatics data sources and specimens. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes were developed and tested on preclinical OSCC cell line and orthotopic OSCC mouse model, fresh OSCC patients’ biopsied samples, and further clinical mouthwash trials were conducted in OSCC patients.ResultsEGFR and PD-L1 were specifically expressed in human OSCC cell lines and tumor xenografts. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes can specifically target to the tumor sites in an in situ human OSCC mouse model with good safety. The detection sensitivity and specificity of Nimotuzumab-ICG in patients were 96.4% and 100%, and 95.2% and 88.9% for Atezolizumab-Cy5.5.ConclusionsEGFR and PD-L1 are highly expressed in OSCC, the combination of which is important for a precise prognosis of OSCC. EGFR and PD-L1 expression can be sensitively detected using the newly synthesized multispectral fluorescence imaging probes Nimotuzumab-ICG and Atezolizumab-Cy5.5, which can facilitate the sensitive and specific detection of OSCC and improve treatment outcomes.Trial registrationChinese Clinical Trial Registry, ChiCTR2100045738. Registered 23 April 2021, https://www.chictr.org.cn/bin/project/edit?pid=125220

AGR2 facilitates teratoma progression by regulating glycolysis via the AnXA2/EGFR axis

Anterior gradient-2 (AGR2) is highly expressed in several tumors and plays an important role in tumor development. However, the biological function of AGR2 in teratomas has not yet been thoroughly studied. In this study, AGR2 was found to be upregulated in teratoma tissues and in human testicular teratoma cell lines by Western blotting and qRT-PCR assays. A DNA Methylation-Specific PCR assay demonstrated that AGR2 upregulation resulted from hypomethylated AGR2 in teratoma cells. NCC-IT and NT2-D1 cells were transfected with pcDNA-AGR2 or sh-AGR2 to obtain AGR2-overexpressed or -silenced cells, and cell proliferation, invasion and glycolysis were determined using CCK-8, 5-ethynyl-2′-deoxyuridine (EdU), Transwell assays, and commercial kits. The results revealed that overexpression of AGR2 promoted teratoma cell proliferation and invasion and elevated glycolysis levels evidencing by the increase in lactate secretion, glucose consumption, ATP levels and the expression of glycolysis-related proteins, while knockdown of AGR2 showed the opposite results. The interactions between AGR2 and annexin A2 (AnXA2), as well as between AnXA2 and epidermal growth factor receptor (EGFR) were verified by co-immunoprecipitation assay. Mechanistic studies revealed that AGR2 interacts with AnXA2 and increases the level of AnXA2 to recruit more AnXA2 to EGFR, there by promoting EGFR expression. A series of rescue experiments showed that knockdown of AnXA2 or EGFR weakened the promotional effects of AGR2 overexpression on the proliferation, invasion, and glycolysis of teratoma cells. Finally, tumorigenicity assays were performed using NT2-D1 cells stably transfected with either LV-NC-shRNA or LV-shAGR2. The results showed that AGR2 knockdown significantly inhibited teratoma tumor growth in vivo. In conclusion, our data suggested that AGR2 facilitates glycolysis in teratomas through promoting EGFR expression by interacting with AnXA2, thereby promoting teratoma cells proliferation and invasion.

Silencing Nrf2 in cisplatin resistant non-small cell lung cancer cells augments sensitivity towards EGFR inhibitor

Recently, non-small cell lung cancer (NSCLC) has been the prime concern of cancer clinicians due to its high mortality rate worldwide. Cisplatin, a platinum derivative, has been used as a therapeutic option for treating metastatic NSCLC for several years. However, acquired, or intrinsic drug resistance to Cisplatin is the major obstacle to the successful treatment outcome of patients. Dysregulation of Nrf2 (nuclear factor erythroid 2-related factor 2) and EGFR (epidermal growth factor receptor) signaling have been associated with cellular proliferation, cancer initiation, progression and confer drug resistance to several therapeutic agents including Cisplatin in various cancers. To dissect the molecular mechanism of EGFR activation in resistant cells, we developed Cisplatin-resistant (CisR) human NSCLC cell lines (A549 and NCIH460) with increasing doses of Cisplatin treatment over a 3-month period. CisR cells demonstrated increased proliferative capacity, clonogenic survivability and drug efflux activity compared to the untreated parental (PT) cells. These resistant cells also showed higher levels of Nrf2 and EGFR expression. Here, we found that Nrf2 upregulates both basal and inducible expression of EGFR in these CisR cells at the transcriptional level. Moreover, genetic inhibition of Nrf2 with siRNA in CisR cells showed increased sensitivity towards the EGFR tyrosine kinase inhibitor (TKIs), AG1478. Our study, therefore suggests the use of Nrf2 inhibitors in combinatorial therapy with EGFR TKIs for the treatment of resistant NSCLC.

Kurarinol restrains non-alcoholic fatty liver disease-associated hepatocellular carcinoma (HCC) progression by suppressing EGFR signaling

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a key factor for hepatocellular carcinoma (HCC) development. As a metabolic hepatic damage, there is still a lack of efficient therapy for NAFLD-HCC. Kurarinol (KUR) is a flavanone extracted from the root of Sophora flavescens, and exerts excellent hepatoprotective and lipid-lowering activities. But its potential on NAFLD-HCC still remains unclear, and thus was explored in our present study. Firstly, in vitro experiments revealed that KUR treatments markedly reduced lipid deposition and inflammatory response in hepatocytes under palmitate and oleic acid stimulation (PO) with decreased expression levels of fatty acid synthesis markers including fatty acid synthase (FASN), stearoyl-CoA desaturase-1 (SCD1) and sterol receptor element binding protein-1 (SREBP-1). Importantly, the proliferation of HCC cell lines was strongly limited by KUR in a dose-dependent manner. Of note, PO stimulation accelerated the proliferative capacity of HCC cells, whereas being significantly suppressed by KUR. Mechanistically, we found that epidermal growth factor receptor (EGFR) and its phosphorylation protein expression levels were highly down-regulated in hepatocytes and HCC cell lines under PO stimuli. More importantly, the functions of KUR to restrain lipid accumulation and HCC cell proliferation were diminished upon EGFR overexpression, confirming that EGFR suppression was necessary for KUR to treat NAFLD-HCC. Murine mouse models were finally established by the use of diethylnitrosamine (DEN) with high-fat/high-cholesterol diet (HFHC) feeding to determine the role of KUR in NAFLD-HCC. Oral gavage of KUR efficiently suppressed NAFLD-HCC formation in mice, as evidenced by the decreased tumor number and loading. KUR also ameliorated lipid accumulation, liver dysfunction, fibrosis and HCC cell proliferation in DEN/HFHC-challenged mice, along with decreased EGFR expression. Collectively, KUR may be an effective strategy for NAFLD-HCC prevention via EGFR signaling suppression.

Inhibitory effects of Gracilaria edulis and Gracilaria salicornia against the MGMT and VEGFA biomarkers involved in the onset and advancement of glioblastoma using insilico and invitro approaches.

Glioblastoma (GBM), an aggressive primary brain tumor originating from glial cells, poses significant treatment challenges due to its rapid growth and invasiveness. The exact mechanisms of GBM's brain damage remain unclear. This study examines primary molecular markers commonly assessed in GBM patients, including brain-derived neurotrophic factor (BDNF), platelet-derived growth factor receptor A (PDGFRA), O6-methylguanine DNA methyltransferase (MGMT), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor A (VEGFA) using computational approaches. The study revealed significant differences (p ≤ 0.05) in PDGFRA, EGFR, and VEGFA expression rates, which are particularly interesting. Additionally, MGMT and VEGFA showed higher hazard ratios. Expression levels of MGMT and VEGFA were visualized in immune and malignant cells using single-cell RNA datasets GSE103224 and GSE148842. From a total of 48 compounds in Gracilaria edulis and 86 in Gracilaria salicornia, we identified 15 compounds capable of crossing the blood-brain barrier. Notably, 2-tridecanone (binding affinity [BA] = -4.2kcal/mol; root mean square deviation [RMSD] = 1.479Å) and decanoic acid, ethyl ester (BA = -4.2kcal/mol; RMSD = 1.702Å) from G. edulis interacted with MGMT via hydrogen bonds. The compound alpha-terpineol interacted with MGMT (BA = -5.7kcal/mol; RMSD = 0.501Å) and VEGFA (BA = -4.7kcal/mol; RMSD = 2.483Å). Ethanolic and methanolic extracts from G. edulis and G. salicornia demonstrated mild anti-cell proliferation properties in the GBM LN-229 cell line, suggesting potential therapeutic benefits. This study highlights the significance of molecular markers and natural compounds in understanding and potentially treating GBM.

EGFR mutations and abnormal trafficking in cancers.

Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor and a member of the ErbB receptor family. As a significant cancer driver, EGFR undergoes mutations such as gene amplification or overexpression in a wide range of malignant tumors and is closely associated with tumorigenesis. This review examines the aberrant expression of EGFR in several common cancers and summarizes the current therapeutic strategies developed for this receptor. Additionally, this review compares the differences in EGFR activation, internalization, endocytosis, and sorting in normal and cancer cells, and highlights some regulatory factors that influence its trafficking process.Kindly check and confirm the edit made in the title.Yes, correctAs per journal instructions structured abstract is mandatory kindly provideThe abstract format does not apply to Review articles.

Electrochemiluminescence assay for the impact of Ganoderma lucidum polysaccharides on resisting arsenic-induced apoptosis

Ganoderma lucidum (G. lucidum) is a traditional edible fungus with strong medicinal value. G. lucidum polysaccharides (GLP) encapsulate many of the key beneficial properties of this species, providing a valuable tool for the treatment of a range of diseases. The present study was developed to explore the protective benefits of GLP treatment in the context of arsenic poisoning. Through microscopy and flow cytometry experiments, NaAsO2 was found to induce rat tracheal epithelial (RTE) cell apoptosis, together with reductions in cell surface epidermal growth factor receptor (EGFR) expression. GLP treatment, however, was able to reduce apoptosis rates and elevate the expression of EGFR relative to NaAsO2-treated cells. GLP extracts (50, 100, 200 mg·mL−1) prepared from four types of G. lucidum were administered to RTE cells damaged with arsenic, revealing limited differences in position resistance among these varieties. This work provides reference for the pharmaceutical and medical research of G. lucidum.

Epidermal growth factor receptor and programmed cell death-1 expression levels in peripheral T cell subsets of patients with non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths, in part due to its late diagnosis. Increased epidermal growth factor receptor (EGFR) expression in cancer cells is associated with a poor prognosis, and EGFR tyrosine kinase inhibitors are widely used in cancer treatment. This study aimed to clarify the relationship between EGFR expression on T cells and cancer prognosis in patients with non-small cell lung cancer (NSCLC). Forty patients with NSCLC and 40 healthy volunteers were included in this study. Peripheral CD4+T helper (Th1, Th2, Th9, Th17, Th1Th17, follicular and peripheral Th) and cytotoxic T lymphocyte (CD8+follicular and peripheral T) subsets were identified with flow cytometry according to their chemokine receptors. EGFR expression on T lymphocytes in relation to overall survival (OS) was investigated in patients with NSCLC. The patients [mean age (min-max) = 64.03 (45-83); 20 stage I-III and 20 stage IV] had increased EGFR expression on CD3+T, CD4+Th, Th1, Th2, and Th17 cells compared to the controls (p < 0.05). High EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells was associated with poor OS. Also, PD-1 expression on lymphocytes, CD3+T, and Th cells was increased in patients with NSCLC compared to controls. The high expression of EGFR and PD-1 on Th cells and the reduced percentage of lymphocytes and Th cells, especially in stage IV patients with NSCLC, revealed that increased EGFR activity may trigger apoptosis of Th cells and promote the development of metastases, while high EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells may be an independent poor prognostic marker in NSCLC.

Increased infiltration of M2-polarized tumour-associated macrophages is highly associated with advanced disease stage and high expression of PD-L1 in buccal mucosa carcinoma

ObjectiveTo assess the infiltration characteristics of tumour-associated macrophages (TAMs) in buccal mucosa carcinoma (BMC) and the correlation of these features with clinicopathological factors.Materials and methodsImmunohistochemistry was used to detect the expression of TAM-related markers (CD68, CD163, CD206), CD8+ T cell markers, PD-L1, and epidermal growth factor receptor (EGFR) in 46 patients with mucosal cancer after radical surgery. In addition, the correlation between TAM infiltration and clinical characteristics, PD-L1 expression, and EGFR expression was analysed.ResultsA high infiltration level of M2-polarized (CD206+) TAMs and M2-polarized (CD163+) TAMs was more common in stage T3–T4, N+, III–IV patients than in other patient groups (P < 0.05). The infiltration degree of M2-polarized (CD68+) TAMs was positively correlated with the PD-L1 TPS (P = 0.0331). The infiltration level of M2-polarized (CD206+) TAMs was higher in the EGFR high expression group than in the EGFR low expression group (P = 0.040).ConclusionHigh infiltration of M2-polarized TAMs is highly associated with advanced disease stage and higher expression of PD-L1 and EGFR in BMCs, suggesting that M2-polarized TAMs infiltration can serve as a potential therapeutic target.

Radiolabeling and Preclinical Evaluation of Therapeutic Efficacy of 225Ac-ch806 in Glioblastoma and Colorectal Cancer Xenograft Models.

The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with 225Ac and evaluated its invitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. Methods: 225Ac-ch806 was prepared using different chelators, yielding [225Ac]Ac-macropa-tzPEG3Sq-ch806 and [225Ac]Ac-DOTA-dhPzPEG4-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of 225Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of 225Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis. Results: [225Ac]Ac-macropa-tzPEG3Sq-ch806 surpassed [225Ac]Ac-DOTA-dhPzPEG4-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [225Ac]Ac-macropa-tzPEG3Sq-ch806 was therefore used for both invitro and invivo studies. It displayed a significant, specific, and dose-dependent invitro cell-killing effect in U87MG.de2-7 cells. 225Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues. 225Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in 225Ac-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in all 225Ac-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with 225Ac-ch806. Conclusion: In glioblastoma and colorectal tumor models, 225Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of 225Ac-ch806 as a potential therapy for EGFR-expressing solid tumors.

Association between exposure to organophosphate flame retardants and epidermal growth factor receptor expression in lung cancer patients.

Organophosphate flame retardants (OPFRs) are extensively distributed in our environment, prompting concerns about potential health hazards, including lung injuries resulting from OPFR exposure. The present study recruited 125 lung cancer patients, assessing their exposure to 10 OPFR compounds through urine samples. The final analysis comprised 108 participants after excluding those lacking epidermal growth factor receptor (EGFR) status and those with chronic kidney disease. Demographic and clinical characteristics, as well as urinary OPFR concentrations, were compared based on OPFR detection. Spearman correlation was conducted to explore the relationship between OPFR compounds, while logistic regression was used to identify OPFR compounds associated with EGFR mutation. The study revealed widespread OPFR exposure among lung cancer patients, with an overall detection frequency of 99.07%. Tris(2-butoxyethyl) phosphate (TBEP) exhibited a strong correlation to its metabolite bis(2-butoxyethyl) phosphate (r = 0.88, p < 0.01). Patients with TBEP in their urine had higher percentage of wild-type EGFR and the detection of TBEP was associated with a reduced likelihood of mutant EGFR expression. OPFR exposure was prevalent in lung cancer patients, with TBEP detection identified as a factor with lower EGFR mutation expression. This study contributes to the understanding of OPFR exposure in lung cancer patients and underscores the significance of TBEP in evaluating EGFR mutation in this population.

Prediction of prognosis in lung cancer using machine learning with inter-institutional generalizability: A multicenter cohort study (WJOG15121L: REAL-WIND)

ObjectivesPredicting the prognosis of lung cancer is crucial for providing optimal medical care. However, a method to accurately predict the overall prognosis in patients with stage IV lung cancer, even with the use of machine learning, has not been established. Moreover, the inter-institutional generalizability of such algorithms remains unexplored. This study aimed to establish machine learning-based algorithms with inter-institutional generalizability to predict prognosis. Materials and MethodsThis multicenter, retrospective, hospital-based cohort study included consecutive patients with stage IV lung cancer who were randomly categorized into the training and independent test cohorts with a 2:1 ratio, respectively. The primary metric to assess algorithm performance was the area under the receiver operating characteristic curve in the independent test cohort. To assess the inter-institutional generalizability of the algorithms, we investigated their ability to predict patient outcomes in the remaining facility after being trained using data from 15 other facilities. ResultsOverall, 6,751 patients (median age, 70 years) were enrolled, and 1,515 (22 %) showed mutated epidermal growth factor receptor expression. The median overall survival was 16.6 (95 % confidence interval, 15.9–17.5) months. Algorithm performance metrics in the test cohort showed that the areas under the curves were 0.90 (95 % confidence interval, 0.88–0.91), 0.85 (0.84–0.87), 0.83 (0.81–0.85), and 0.85 (0.82–0.87) at 180, 360, 720, and 1,080 predicted survival days, respectively. The performance test of 16 algorithms for investigating inter-institutional generalizability showed median areas under the curves of 0.87 (range, 0.84–0.92), 0.84 (0.78–0.88), 0.84 (0.76–0.89), and 0.84 (0.75–0.90) at 180, 360, 720, and 1,080 days, respectively. ConclusionThis study developed machine learning algorithms that could accurately predict the prognosis in patients with stage IV lung cancer with high inter-institutional generalizability. This can enhance the accuracy of prognosis prediction and support informed and shared decision-making in clinical settings.

Theoretical exploring of potential mechanisms of antithrombotic ingredients in danshen-chishao herb-pair by network pharmacological study, molecular docking and zebrafish models

BackgroundSalvia miltiorrhiza (Danshen, DS) and Radix Paeoniae Rubra (Chishao, CS) herbal pair (DS-CS) is a famous traditional Chinese combination which has been used as antithrombotic formular for centuries. However, there is still lack of sufficient scientific evidence to illustrate its underlying mechanisms. The purpose of this study is to investigate the antithrombotic effects of DS-CS extract in zebrafish and explore its possible mechanism of action.MethodsThe quality of traditional Chinese medicines DS and CS granules was evaluated using High Performance Liquid Chromatography (HPLC). Subsequently, the therapeutic effect of the DS-CS combination and its components, Salvianolic Acid A (SAA) and Paeoniflorin (PF), in various concentrations on thrombosis was experimentally validated. Moreover, the interaction between DS-CS and the thrombosis disease targets was analyzed through network pharmacology, predicting the potential antithrombotic mechanism of DS-CS. Molecular docking and in vivo zebrafish experiments were conducted to validate the predicted targets, with qRT-PCR utilized for target validation.ResultsDS-CS exhibited anti-thrombotic effect in zebrafish with concentrations ranging from 25 to 300 μg/mL. The co-administration of PF and SAA at 25 μg/mL each revealed a synergistic antithrombotic effect exceeding that of individual components when contrasted with PHZ treatment. Protein–protein interaction (PPI) analysis identified key genes, including Albumin (ALB), Proto-oncogene tyro-sine-protein kinase Src (SRC), Matrix metalloproteinase-9 (MMP9), Caspase-3 (CASP3), Epidermal growth factor receptor (EGFR), Fibroblast growth factor 2 (FGF2), Vascular endothelial growth factor receptor 2 (KDR), Matrix metalloprotein-ase-2(MMP2), Thrombin (F2), and Coagulation factor Xa (F10), associated with the antithrombotic action of PF and SAA. Furthermore, KEGG pathway analysis indicated involvement of lipid metabolism and atherosclerosis pathways. Molecular docking revealed strong binding of PF and SAA to pivotal hub genes, such as SRC, EGFR, and F10. The experimental findings demonstrated that DS-CS could upregulate the mRNA expression levels of EGFR while inhibiting F10 and SRC mRNA levels, thereby ameliorating thrombotic conditions.ConclusionThis research provided valuable insights into the potential mechanisms underlying the antithrombotic activity of DS-CS. Our findings suggested that PF and SAA could be the key active ingredients responsible for this activity. The antithrombotic effects of DS-CS appeared to be mediated through the regulation of mRNA expression of SRC, EGFR, and F10. These results enhanced our understanding of DS-CS's therapeutic potential and lay the groundwork for future studies to further elucidate its mechanisms of action.

Anticancer activity of Araguspongine C via inducing apoptosis, and inhibition of oxidative stress, inflammation, and EGFR-TK in human lung cancer cells: An in vitro and in vivo study.

The advanced non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor(EGFR) mutations has put a selective pressure on the discovery and development of newer EGFR inhibitors. Therefore, the presentstudy intends to explore the pharmacological effect of Araguspongine C (Aragus-C) as anticancer agent against lung cancer. The effect of Aragus-C was evaluated on the viability of the A549 and H1975 cells. Further biochemical assays were performed to elaborate the effect of Aragus-C, on the apoptosis, cell-cycle analysis, and mitochondrial membrane potential in A549 cells. Western blot analysis was also conducted to determine the expression of EGFR in A549 cells. Tumor xenograft mice model from A549 cells was established to further elaborate the pharmacological activity of Aragus-C. Results suggest that Aragus C showed significant inhibitory activity against A549 cells as compared to H1975 cells. It has been found that Aragus-C causes the induction of apoptosis and promotes cell-cycle arrest at the G2/M phase of A549 cells. It also showed a reduction in the overexpression of EGFR in A549 cells.In tumor xenograft mice model, it showed a significant reduction of tumor volume in a dose-dependent manner, with maximum inhibitory activity was reported by the 8 mg/kg treated group. It also showed significant anti-inflammatory and antioxidant activity by reducing the level of TNF-α, IL-1β, IL-6, and MDA, with a simultaneous increase of superoxide dismutase and glutathione peroxidase. We have demonstrated the potent anti-lung cancer activity of Aragus-C, and it may be considered as a potential therapeutic choice for NSCLC treatment.

Interpretation of Epidermal Growth Factor Receptor Status in Microscopic Tumor-Free Surgical Margins and Lymph Nodes in Patients with Oral Squamous Cell Carcinoma: An Analysis of 125 Margins.

Squamous cell carcinomas are the most common type of oral cancer contributing for around 90%. The overall survival is below 50% for these patients. There is a requirement for a non-invasive marker to predict the prognosis. The epidermal growth factor (EGF) and their receptors (EGFR, ErbB-1) are not only documented to play a critical and an influential role in cell growth and differentiation in normal/healthy tissues, but may also plays an important role in malignant disease progression and tumorigenesis. This study was done to find the significance of EGF receptor expression on microscopic free tumour margins and lymph nodal margins to predict the survival of the patient in a 2-year follow-up. A prospective cohort study of 25 patients was performed in biopsy proven oral squamous cell carcinoma patients who reported to our department from July 2017 to June 2019. The data were collected from their histopathological report, they were- pTNM staging, surgical margins (superior and inferior, anterior, posterior), nodal status and scoring of EGFR expression on wax blocks was done. Total of 125 wax blocks were analysed for the study. Follow-up of 2years were recorded in the study to evaluate the survival of the patients. The expression of EGFR on microscopic tumour-free surgical margins and lymph nodes was p value 0.023 which was statistically significant. The level of significance between EGFR and status of patients after 2-year follow-up was having p value 0.031. Out of 25 patients, 5 patients were dead at a 2-year follow-up. Out of these 5 patients who were dead, 3 patients had a local recurrence and 2 patients had distant metastasis. This cohort study concludes that EGFR is an important prognostic marker and must be analysed in all microscopic tumour-free margins and lymph nodes in advanced oral squamous cell carcinomas to predict the local recurrences affecting the survival of the patients and the need for addition of anti-EGFR agents in adjuvant treatment. Since the sample size is small, large scale studied must be done to validate the need for adding anti-EGFR agents in adjuvant treatment to improve the survival of patients.

Immunohistochemical assessment of epidermal growth factor receptor and prohibitin expression in “post-COVID” placentas: results of a comparative cross-sectional study

Background. COVID-19 pandemic is accompanied by a considerable number of morbidity cases among pregnant women. Certain knowledge has been accumulated about the histopathological features of the placenta during SARS-CoV-2 infection. Specific proteomic studies of the function of the placenta are insufficient.Objective of the study: to study the perinatal outcomes of pregnancy and histopathological features of the placenta and the expression of epidermal growth factor receptors (EFGR) and prohibitin (PHB) in the placenta in pregnant women with COVID-19 infection in comparison with data in a group of healthy pregnant women without a COVID-19 history.Materials and methods. 58 pregnant women with COVID-19 infection during pregnancy and 40 healthy pregnant women were examined at the base of Maternity Hospital No. 2 of the Odessa City Council. A histological and immunohistochemical study of placentas was carried out for the expression of EFGR and PHB In addition to a general clinical examination. Results. A higher frequency of premature births (15.51% vs 5%) and cesarean sections (34.4% vs 12.5%) in the “post-COVID” group was revealed. Most women fell ill in the third trimester of pregnancy (65.51%). A significant difference was found in Apgar scores in the groups (6.48 ± 2.39 vs 8.05 ± 0.54 points), in the weight of newborns (3067.93 ± 620.21 g vs 3617.25 ± 354.58 g). In the placentas of the “post-COVID” group, signs of mother’s (53.45% vs 12.5%) and fetus’ vascular malperfusion (32.7% vs 15%) were detected with greater frequency; as well as hemodynamic disturbances (53.45% vs 15%). Analysis of EFGR expression in the groups showed no differences (2.96 ± 0.2 vs 2.75 ± 0.44) in contrast to PHB (1.52 ± 1.12 vs 0.25 ± 0.5), which was characterized by overexpression in the women with COVID-19. Conclusions. SARS-CoV-2 infection during pregnancy is associated with certain changes in placental metabolism, and changes in the expression of placental proteins EGFR and PHB may be involved in the pathogenetic mechanisms of the placental dysfunction development. The limited sample size requires additional research.