Epidermal Growth Research Articles

Effect of SMARCA4 mutations on the outcomes of patients with advanced EGFR mutant lung adenocarcinoma

Objective: To investigate the impact of SMARCA4 mutations on the outcomes of patients with advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Methods: In the Memorial Sloan Kettering Cancer Center (MSK) MetTropism study, 960 patients with advanced EGFR-mutated lung adenocarcinoma were screened and included in the MSK cohort, composing of 313 males and 647 females, with a median [M(Q1, Q3)] age of 64 (56, 72) years. A retrospective analysis was conducted on the data of 178 patients with advanced EGFR-mutated lung adenocarcinoma who received EGFR tyrosine kinase inhibitors (TKIs) treatment in the Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, from January 2018 to December 2022. Among these patients, 69 were males and 109 were females, with a median age of 63 (54, 69) years. The follow-up of patients from the First Affiliated Hospital of Nanjing Medical University was conducted up to December 31, 2023, with a median follow-up time of 26.6 (95%CI: 24.6-28.6) months for the entire cohort, and 29 patients were lost to follow-up. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the relationship between SMARCA4 gene alternations and prognosis. Results: In the 960 patients of the MSK cohort with advanced EGFR-mutated lung adenocarcinoma, the SMARCA4 gene alternations rate was 4.2% (40/960). The median overall survival (OS) for patients without SMARCA4 gene alternations was 41.5 (95%CI: 35.6-47.3) months, which was superior to that of patients with SMARCA4 gene alternations [15.6 (95%CI: 7.9-23.4) months, P<0.001]. Patients with SMARCA4 gene alternations had a higher risk of mortality, with an HR (95%CI) of 1.97 (1.35 to 2.88). Among the 178 patients with advanced EGFR-mutated lung adenocarcinoma from the First Affiliated Hospital of Nanjing Medical University, the SMARCA4 gene alternations rate was 4.5% (8/178). The median progression-free survival (PFS) for patients without SMARCA4 gene alternations was 16.1 (95%CI: 12.2-20.0) months, which was superior to the median PFS of patients with SMARCA4 gene alternations [6.0 (95%CI: 1.3-10.7) months, P<0.001]. The median OS for patients without SMARCA4 gene alternations was 50.1 (95%CI: 28.1-72.1) months, which was also superior to the median OS of patients with SMARCA4 gene alternations [17.6 (95%CI: 15.4-19.8) months, P=0.001]. Conclusion: SMARCA4 alternation is an important factor associated with poor prognosis in patients with advanced EGFR-mutant lung adenocarcinoma.

Germline BRCA testing in Denmark following invasive breast cancer: Progress since 2000.

Despite advancements in genetic testing and expanded eligibility criteria, underutilisation of germline testing for pathogenic variants in BRCA1 and BRCA2 (BRCA) remains evident among breast cancer (BC) patients. This observational cohort study presents real-world data on BRCA testing within the context of clinical practice challenges, including incomplete family history and under-referral. From the Danish Breast Cancer Group (DBCG) clinical database, we included 65,117 females with unilateral stage I-III BC diagnosed in 2000-2017, of whom 9,125 (14%) were BRCA tested. Test results spanned from 1999 to 2021. We evaluated test rates overall and in three diagnosis periods. In logistic regression models, we examined the correlation between a BRCA test and patients' age, residency region, receptor status, and diagnosis period. Test rates rose most significantly among patients aged under 40 years, increasing from 47% (2000-2005) to 88% (2012-2017), albeit with regional discrepancies. Test timing shifted in recent years, with most results within 6 months of BC diagnosis, primarily among the youngest patients. BRCA test rates were higher for oestrogen receptor-negative/human epidermal growth factor receptor 2-negative BC (25% in 2000-2005 vs. 38% in 2012-2017), and these findings were confirmed in multivariate regression models. Our results indicate a critical need for an intensified focus on BRCA testing among BC patients older than 40, where a mainstreamed testing approach might overcome delayed or missed testing. Current DBCG guidelines recommend BRCA testing of all BC patients younger than 50 years, while a general recommendation for older patients is still missing.

Electrochemical capacitance-based aptasensor for HER2 detection.

The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) protein is specifically related to tumor cell proliferation in breast cancers. Its presence in biological serum samples indicates presence or progression of cancer, becoming a promise biomarker. However, their detection needs a simple and high accuracy platform. In this study, we report the develop and optimization of a simple highly sensitive electrochemical platform for HER2. Gold electrode surface was modified with a self-assembled monolayer composed by DNA aptamer, 6-(ferrocenyl) hexanethiol and 6-mercapto-1-hexanethiol. Electrochemical impedance spectroscopy was used to quantify the changes in capacitance on the interface due to the presence ferrocene, whether acting as a redox charge or its behavior under different HER2 concentration in PBS and undiluted human serum. As a result, the approach allows detection of HER2 with a limit of detection of 3.61 pg/mL, 12.28 nF sensitivity per decade and a linear range from 1 pM to 1 [Formula: see text]M in serum. This electrochemical aptasensor can be applied to different arrays for aptamer screening and has a significant importance to interaction study of biological systems.

HER2 regulates autophagy and promotes migration in gastric cancer cells through the cGAS-STING pathway.

In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment. Through lentiviral transfection, cell counting kit-8 assays, colony formation, transwell migration, scratch assays, and siRNA, we found that HER2 overexpression suppresses the cGAS-STING pathway, inhibits autophagy, and enhances the migratory ability of gastric cancer cells. In contrast, HER2 knockdown activates the cGAS-STING pathway, promotes autophagy, and reduces cell migration. We further observed that the inhibition of autophagy using chloroquine (CQ) increases the migration ability of HER2-overexpressing cells. Moreover, interfering with STING expression reversed the migration defects caused by HER2 knockdown, underscoring the critical role of the cGAS-STING pathway in HER2-regulated cell migration. We also revealed that high STING expression in gastric cancer is significantly associated with poor prognosis. STING expression was identified as an independent prognostic factor for survival (hazard ratio, 1.942; 95% confidence interval, 1.06-3.54; P = 0.031). These results highlight the importance of HER2-driven regulation of autophagy through the cGAS-STING pathway in gastric cancer progression and its potential as a therapeutic target.

Respiratory complex I-mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7.

The role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)-mediated NAD+ regeneration is important for cancer cell proliferation. In cancer cells, a decrease in CI activity by RNA interference (RNAi) against NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1) arrested the cell cycle at the G1/S phase, accompanying upregulation of p21Cip1 cyclin-dependent kinase inhibitor expression. Mechanistically, a decrease in the NAD+/NADH ratio downregulated SIRT3 and SIRT7 function, which suppressed p21Cip1 expression at the translational and transcriptional levels, respectively, resulting in the upregulation of the antiproliferative molecule. Importantly, high expression levels of the core subunits of CI correlated with poor prognosis in patients with the hormone receptor(+)/human epidermal growth factor receptor 2(-) (HR+/HER2-) subtype of breast cancer. Therefore, NDUFV1 and SIRT3/7 have emerged as promising therapeutic targets against this breast cancer subtype.

Inavolisib: First Approval.

Inavolisib (Itovebi™) is an orally administered, phosphatidylinositol-3-kinase alpha (PI3Kα) inhibitor being developed by Genentech, a member of the Roche group, for the treatment of solid tumours. On 10 October 2024, inavolisib received its first approval in the USA in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. In the EU and other countries worldwide, regulatory review of inavolisib is currently underway. This article summarises the milestones in the development of inavolisib leading to this first approval for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

Effect of Epidermal Growth Factor in a Patient with Diabetic Hand

Effect of Epidermal Growth Factor in a Patient with Diabetic Hand

Real‑world therapeutic strategies and survival outcomes in advanced HER2-mutant non-small cell lung cancer.

Limited information is available regarding the clinical features and outcomes of advanced human epidermal growth factor receptor 2 (HER2)-mutant non-small cell lung cancer (NSCLC) in Taiwan, despite expanding treatment options for this distinct subtype. The present study explored the clinical features and outcomes of HER2-mutant NSCLC in a real-world setting. Relevant data were collected from patients with advanced or recurrent HER2-mutant NSCLC who received systemic therapy between 2011 and 2021 and were followed up until 2022 at two medical centers in Taiwan. Clinical features, treatment responses, and survival-associated factors were analyzed. This study included 45 patients (median age: 59.7 [range: 41.3-78.7] years). A775_G776insYVMA was the most common NSCLC subtype (57.8%), followed by G778_P780dup (11.1%). Approximately 53.3% of the patients received first-line platinum-based chemotherapy (PC) alone, whereas 13.3% received PC combined with an immune checkpoint inhibitor (ICI). The median overall survival (OS) and progression-free survival (PFS) after first-line therapy were 25.8 and 4.4 months, respectively. The objective response rate was generally higher in patients receiving first-line PC + ICI than in those receiving PC alone (33.3% vs. 12.5%; p = 0.269). Furthermore, patients receiving PC + ICI had longer PFS than did those receiving PC alone (9.5 vs. 4.4 months; p = 0.131) and those receiving tyrosine kinase inhibitor/ICI monotherapy (9.5 vs. 0.5 months; p = 0.015). Compared with patients having other NSCLC subtypes, those carrying HER2 exon 20 insertion mutations had shorter median PFS (17.3 vs. 2.9 months; p = 0.043) and OS (not reached vs. 19 months; p = 0.031). This study highlights the clinical features and outcomes of advanced HER2-mutant NSCLC in Taiwan. PC + ICI may be more effective than other regimens as first-line therapy. The prognostic role of HER2 exon 20 insertion mutations warrants further investigation.

HER2 expression and pathway status in male breast cancer patients: results of an integrated analysis among 6,150 patients

The role of human epidermal growth factor 2 (HER2) in male breast cancer (MBC) is poorly defined. A comprehensive description of HER2 status was conducted. A total of 6,015 MBC patients from 45 studies and 135 MBC patients with sequencing data were identified. HER2 positive rates and hazard ratios (HR) for overall survival (OS) were combined using Metaprop. The prevalence of HER2 + MBC was 10.0% (95% CI: 8.0-13.0%). Subgroup analyses showed that 7% (95% CI: 2.0-14.0%) had HER2 + protein overexpression. 10% of MBC patients had HER2 + overexpression and/or gene amplification. Asian MBC patients had the highest HER2 + incidence of 17% (95% CI: 12.0-22.0%). The prevalence of HER2 positive MBC fluctuated widely from 2001 to 2015 and then stabilized at 10%. HER2 positivity was significantly correlated with worse OS than negative ones (HR = 1.92, 1.47–2.51). The proportion of HER2 + MBC was inconsistent with the results for the intrinsic HER2-enriched subtype. Altered genes in HER2 + MBC, such as ERBB2, AGO2, RECQL4, and CLTC, were not detected in HER2-MBC. Genomic analysis revealed differences between the patients with HER2 + MBC and those with HER2 + FBC. The percentage of HER2 + MBC was slightly lower than that of women. Multiple approaches may be needed to jointly assess HER2 status in MBC.

Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt.

The intracellular protozoan Toxoplasma gondii manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis. This raises the possibility that T. gondii activates a signaling mechanism independently of EGFR to avoid autophagic targeting. We report T. gondii activates Src to promote parasite survival even in cells that lack EGFR. Blockade of Src triggered LC3 and LAMP-1 recruitment around the parasitophorous vacuole (PV) and parasite killing dependent on the autophagy protein, ULK1, and lysosomal enzymes. Src promoted PI3K activation and recruitment of activated Akt to the PV membrane. T. gondii promoted Src association with PTEN, and PTEN phosphorylation at Y240, S380, T382, and T383, hallmarks of an inactive PTEN conformation known to maintain Akt activation. Blockade of parasite killing was dependent of activated Akt. Src knockdown or treatment with the Src family kinase inhibitor, Saracatinib, impaired these events, leading to PTEN accumulation around the PV and a reduction in activated Akt recruitment at this site. Saracatinib treatment in mice with pre-established cerebral and ocular toxoplasmosis promoted PTEN recruitment around tachyzoites in neural tissue impairing recruitment of activated Akt, profoundly reducing parasite load and neural histopathology that were dependent of the autophagy protein, Beclin 1. Our studies uncovered an EGFR-independent pathway activated by T. gondii that enables its survival and is central to the development of neural toxoplasmosis.

Predictive factors for axillary pathological complete response to neoadjuvant therapy in elderly breast cancer patients

PurposeThis study explores the predictive factors for axillary pathological complete response(apCR) during neoadjuvant therapy(NAT) for elderly breast cancer patients to supplement the indications for retaining the axilla.MethodsComprehensive clinical information was gathered from November 2016 to July 2023 from elderly patients with pathology-confirmed invasive breast cancer who underwent NAT and surgery in the Breast Department of Sichuan Cancer Hospital. The relationships between clinicopathological characteristics and apCR were investigated via retrospective analysis. Univariate analysis of the clinicopathological parameters and efficacy was performed via the chi-square test or Fisher’s exact test, while multivariate analysis was conducted via binary logistic regression.ResultsThis study included 109 elderly patients with breast cancer, with an overall apCR rate of 46.8%. The univariate analysis results showed that the initial clinical lymph nodes negative(cN0) stage, Human Epidermal Growth Factor Receptor 2(HER2) positivity and breast pathological complete response(bpCR) were significantly correlated with high apCR rates(all P < 0.05). Multivariate analysis revealed that apCR exhibited a significant association with initial cN0 stage and HER2 positivity. The apCR rate for HER2-positive elderly patients with initial cN0 disease is 100.0%,whereas the lowest apCR rate is observed in HER2-negative and clinical lymph nodes positive(cN+) patients(36.0%). Subgroup analysis revealed a close relationship between molecular subtypes and apCR.ConclusionThis study indicates that initial cN0 stage and HER2 positivity can serve as independent predictive factors for apCR after NAT in elderly breast cancer patients. HER2-positive elderly patients with initial cN0 stage can be considered exempt from axillary lymph node dissection(ALND) after standard NAT.

Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.

Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether 23 and biaryl 36 as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne 5 which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CLint compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.

Suitability of different cytological preparations for molecular analysis of advanced NSCLC.

Around 85% of non-small cell lung cancers (NSCLCs) are diagnosed at an advanced stage (IIIB to IV), where therapeutic options depend on molecular analysis. However, diagnostic material for molecular testing is often represented by cytological samples which are generally scarce and span a wide range of preparation types. Thus, the primary objective is to efficiently manage materials for molecular profiling. This study aims to evaluate the suitability of different cytological samples to assess morphological and molecular characteristics of advanced NSCLC. Sixty-seven cytological samples obtained from patients with advanced NSCLC were utilized. The series encompassed different procedure types (fine-needle aspiration cytology, transbronchial needle aspiration, effusions) processed by cell blocks in 54% (n=36), direct smears in 33% (n=22), and Liquid Based Cytology (LBC) in 13% (n=9). Cytological diagnoses were routinely performed and molecular analysis were conducted using NGS and RT-PCR methods. Adequate quantity and quality of nucleic acids were obtained from all the samples, allowing molecular profiling. Combined Next Generation Sequencing (NGS) and Real Time-Polymerase Chain Reaction (RT-PCR) analysis showed wild-type profiles in 62.7% (n=42) and mutated profiles in 37.3% (n=25) of the samples. Kirsten Rat Sarcoma Virus (KRAS) mutations were identified in 19.5% (n=13) of samples, Epidermal Growth Factor Receptor (EGFR) mutations in 10.4% (n=7) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations in 2.9% (n=2). Identified chromosomal alterations were v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) duplication in 2,9% (n=2). The cytological sample types examined in this study proved to be suitable for molecular testing, in addition to conventional morphologic diagnosis, showing versatility and adaptability to different clinical contexts. Molecular testing on cytological samples is accurate and fast, representing a valid tool for molecular profiling of advanced NSCLC.

Downregulation of AATK enhances susceptibility to ferroptosis by promoting endosome recycling in gefitinib-resistant lung cancer cells.

Ferroptosis has been characterised by disruption of the cell membrane through iron-related lipid peroxidation. However, regulation of iron homeostasis in lung cancer cells that are resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains unclear. Transcriptome analysis identified a significant downregulation of apoptosis-associated tyrosine kinase (AATK) mRNA expression in gefitinib-resistant PC9 (PC9-GR) cells, which were found to be more susceptible to ferroptosis inducers. An in-depth analysis of publicly available datasets revealed that downregulation of AATK mRNA was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. Knockdown of AATK-sensitised PC9, HCC827, and H441 cells to the ferroptosis inducer RSL3, whereas ectopic expression of AATK reduced RSL3-induced cell death in PC9-GR and HCC827-GR cells. Compared to PC9 cells, PC9-GR cells exhibited higher transferrin uptake, endosome recycling rate, and increased intracellular iron levels. Blocking iron transport reduced RSL3-induced ferroptosis in PC9-GR cells. Mechanistic studies showed that AATK localised to both early and recycling endosomes. Knockdown of AATK facilitated endosome recycling and elevated intracellular ferrous iron (Fe2+) levels in PC9 cells. Conversely, ectopic expression of AATK delayed endosome recycling and reduced intracellular Fe2+ levels in PC9-GR cells. Inhibition of AATK downregulation-induced iron accumulation decreased RSL3-induced ferroptosis. Taken together, our study indicates that the downregulation of AATK contributes to endosome recycling and iron accumulation, leading to an increased susceptibility to ferroptosis in EGFR-TKI-resistant lung cancer cells. © 2025 The Pathological Society of Great Britain and Ireland.

Non-invasive Assessment of Human Epidermal Growth Factor Receptor 2 Expression in Gastric Cancer Based on Deep Learning: AComputed Tomography-based Multicenter Study.

The expression of human epidermal growth factor receptor 2 (HER2) in gastric cancer is closely associated with its treatment outcomes and prognosis. This study aims to develop and validate a HER2 prediction model based on computed tomography (CT). Additionally, the study evaluates the robustness of the proposed model. This retrospective study included 1059 patients from three hospitals (A, B, and C), where patients from hospitals A and B formed the training set (720 cases), and patients from hospital C served as the external test set (339 cases). Venous-phase CT radiomic features were extracted, normalized using the Z-score method, and simplified via principal component analysis. Feature selection was performed using recursive feature elimination (RFE), analysis of variance, Relief, and the Kruskal-Wallis (KW) test, followed by modeling using Lasso-regularized logistic regression and Support Vector Machine (SVM) methods. The models were evaluated and validated using the area under the curve (AUC) and decision curve analysis to determine the best-performing model. The positive proportions of HER2 expression were 8.60% (52/658) in the training set and 5.60% (19/320) in the test set. Eight distinct models were developed to predict HER2 expression. Among these, the model utilizing RFEand Lasso-regularized logistic regression (LR-Lasso) exhibited the highest predictive performance, with AUC values of 0.7874 (95% CI: 0.7346-0.8402) in the training set and 0.8033 (95% CI: 0.7288-0.8788) in the test set. Compared to other models, this model provided a greater net benefit on the decision curve analysis. These results suggest that the proposed model can be effectively applied to predict HER2 expression in patients. The HER2 prediction model demonstrated promising performance in predicting HER2 expression in gastric cancer patients.

In Silico Born Designed Anti-EGFR Aptamer Gol1 Has Anti-Proliferative Potential for Patient Glioblastoma Cells

The epidermal growth factor receptor (EGFR) is one of the key oncomarkers in glioblastoma (GB) biomedical research. High levels of EGFR expression and mutations have been found in many GB patients, making the EGFR an attractive target for therapeutic treatment. The EGFRvIII mutant is the most studied, it is not found in normal cells and is positively associated with tumor cell aggressiveness and poor patient prognosis, not to mention there is a possibility of it being a tumor stem cell marker. Some anti-EGFR DNA aptamers have already been selected, including the aptamer U2. The goal of this study was to construct a more stable derivative of the aptamer U2, while not ruining its functional potential toward cell cultures from GB patients. A multiloop motif in a putative secondary structure of the aptamer U2 was taken as a key feature to design a novel minimal aptamer, Gol1, using molecular dynamics simulations for predicted 3D models. It turned out that the aptamer Gol1 has a similar putative secondary structure, with G-C base pairs providing its stability. The anti-proliferative activities of the aptamer Gol1 were assessed using patient-derived GB continuous cell cultures, G01 and BU881, with different abundances of EGFR and EGFRvIII. The transcriptome data for the cell culture G01, after aptamer Gol1 treatment, revealed significant changes in gene expression; it induced the transcription of genes associated with neurogenesis and cell differentiation, and it decreased the transcription of genes mediating key nuclear processes. There were significant changes in the gene transcription of key pro-oncogenic signaling pathways mediated by the EGFR. Therefore, the aptamer Gol1 could potentially be an efficient molecule for translation into biomedicine, in order to develop targeted therapy for GB patients.

Antitumor Activities of a Humanized Cancer-Specific Anti-HER2 Monoclonal Antibody, humH2Mab-250 in Human Breast Cancer Xenografts

Monoclonal antibody (mAb) and cell-based immunotherapies represent cutting-edge strategies for cancer treatment. However, safety concerns persist due to the potential targeting of normal cells that express reactive antigens. Therefore, it is crucial to develop cancer-specific mAbs (CasMabs) that can bind to cancer-specific antigens and exhibit antitumor activity in vivo, thereby reducing the risk of adverse effects. We previously screened mAbs targeting human epidermal growth factor receptor 2 (HER2) and successfully developed a cancer-specific anti-HER2 mAb, H2Mab-250/H2CasMab-2 (mouse IgG1, kappa). In this study, we assessed both the in vitro and in vivo antitumor efficacy of the humanized H2Mab-250 (humH2Mab-250). Although humH2Mab-250 showed lower reactivity to HER2-overexpressed Chinese hamster ovary-K1 (CHO/HER2) and breast cancer cell lines (BT-474 and SK-BR-3) than trastuzumab in flow cytometry, both humH2Mab-250 and trastuzumab showed similar antibody-dependent cellular cytotoxicity (ADCC) against CHO/HER2 and the breast cancer cell lines in the presence of effector splenocytes. In addition, humH2Mab-250 exhibited significant complement-dependent cellular cytotoxicity (CDC) in CHO/HER2 and the breast cancer cell lines compared to trastuzumab. Furthermore, humH2Mab-250 possesses compatible in vivo antitumor effects against CHO/HER2 and breast cancer xenografts with trastuzumab. These findings highlight the distinct roles of ADCC and CDC in the antitumor effects of humH2Mab-250 and trastuzumab and suggest a potential direction for the clinical development of humH2Mab-250 for HER2-positive tumors.

Epiregulin ameliorates ovariectomy-induced bone loss through orchestrating the differentiation of osteoblasts and osteoclasts.

Epiregulin plays a role in a range of biological activities including malignancies. This study aims to investigate the potential contribution of epiregulin to bone cell differentiation and bone homeostasis. The data showed that epiregulin expression was upregulated during osteogenesis but downregulated during adipogenesis. Functionally, epiregulin promoted osteoblast differentiation while inhibiting adipocyte differentiation from mesenchymal progenitor cells. Epidermal growth factor receptor (EGFR), one of the two known receptors for epiregulin, exerted opposing effects compared to epiregulin. Intriguingly, silencing EGFR almost completely abolished the dysregulation of osteoblast and adipocyte differentiation induced by epiregulin, suggesting that EGFR is indispensable for mediating epiregulin function. Further mechanistic exploration indicated that epiregulin/EGFR signaled via the inactivation of mechanistic target of rapamycin complex 1 (mTORC1) pathway. Moreover, epiregulin downregulated receptor activator of nuclear factor-κB ligand (RANKL) expression in BMSCs and inhibited the differentiation of bone marrow osteoclast precursor cells into osteoclasts. Treatment of ovariectomized female mice with recombinant epiregulin increased osteoblasts and bone formation, decreased osteoclasts and bone resorption, and ameliorated cancellous bone loss. Consistently, epiregulin treatment improved the potential of BMSCs to differentiate into osteoblasts. Collectively, this study has identified a critical role of epiregulin in regulating osteoblast differentiation through EGFR-mediated inactivation of mTORC1 pathway, as well as osteoclast differentiation via a mechanism associated with RANKL signaling. Additionally, it highlights the potential of epiregulin as a strategy for combating osteoporosis.

The clinical effects and mechanism of action of ranibizumab in treating myopic choroidal neovascularization

PurposeMyopic choroidal neovascularization (CNV) is a common reason for visual impairment. This study investigated the clinical effects of repeated intravitreal injections of ranibizumab among patients with CNV secondary to pathologic myopia.MethodsThis study involved a single-center, non-randomized clinical prospective cohort research design including 39 patients with myopic CNV and a control group of 10 patients with cataract. Plasma and aqueous humor samples were analyzed to compare cytokine concentrations between the two groups and assess changes after intravitreal ranibizumab injections. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) were also monitored.ResultsBCVA values and CMT varied significantly after intravitreal ranibizumab injections. The study group had significantly higher plasma concentrations of vascular endothelial growth factor (VEGF)-A and significantly lower epidermal growth factor (EGF) and angiopoietin-2 concentrations than the control group. Likewise, in the aqueous humor, the study group had significantly higher concentrations of fibroblast growth factor and significantly lower concentrations of EGF and VEGF-A than the control group. The average VEGF-A content decreased significantly after 1 and 2 months relative to the baseline. Mean VEGF-D and endoglin contents at two months were significantly reduced compared to the baseline and at 1 month. The average EGF contents were significantly higher at 2 months than the baseline.ConclusionRanibizumab could increase the BCVA and lower the CMT and cytokines involved in angiogenesis. This study contributes to further understanding the pathogenesis of myopic CNV and promoting new drug research and development for patients with this condition.

Population pharmacokinetics of erlotinib in patients with non-small cell lung cancer (NSCLC): A model-based meta-analysis.

Erlotinib is a potent first-generation epidermal growth factor receptor tyrosine kinase inhibitor. Due to its proximity to the upper limit of tolerability, dose adjustments are often necessary to manage potential adverse reactions resulting from its pharmacokinetic (PK) variability. Population PK studies of erlotinib were identified using PubMed databases. Simulations of erlotinib concentrations were conducted at 4-h intervals, with covariate simulations based on patient characteristics. Three studies were included in this analysis. The one-compartment model was determined to be the most suitable for describing the population PK of erlotinib. A decrease in clearance was observed with age, while an increase in clearance was noted in smoking patients. The volume of distribution was positively correlated with body weight. Our study proposes optimal dosing of erlotinib based on age and smoking status, categorizing the patient population into six groups. This is the first report on a model-based meta-analysis approach to develop a population PK model of erlotinib in patients with non-small cell lung cancer. Our findings suggest that an increased dosage is appropriate for patients under 60 who smoke, whereas a reduced dosage is more suitable for non-smoking older patients.