Expression Of Growth Factor Receptor Research Articles

Phase 1/2 study of the HER3-directed antibody-drug conjugate patritumab deruxtecan (MK-1022) as monotherapy in patients with gastrointestinal cancers.

TPS321 Background: A significant medical need exists for more effective and tolerable therapeutic options for patients with advanced gastrointestinal cancers (colorectal cancer [CRC], biliary tract cancer [BTC], and hepatocellular carcinoma [HCC]). Human epidermal growth factor receptor (HER3) expression is high in CRC and BTC, and low-to-intermediate in HCC. Patritumab deruxtecan (HER3-DXd; U3-1402/MK-1022) is a HER3-directed antibody-drug conjugate (ADC) comprising a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab), which includes a plasma-stable, selectively cleavable linker, and a potent topoisomerase I inhibitor payload (DXd; released payload) that leverages the clinically validated deruxtecan (a derivative of exatecan) technology. DXd is cell membrane permeable and enables a bystander antitumor effect after DXd ADC internalization and linker cleavage, resulting in elimination of both target and neighboring tumor cells. Patritumab deruxtecan has shown antitumor activity in phase 1 and 2 studies of EGFR-mutated advanced non–small cell lung cancer and advanced breast cancer and in preclinical studies of CRC. This nonrandomized, open-label, phase 1/2 study (NCT06596694) will examine the safety and efficacy of patritumab deruxtecan in select gastrointestinal cancers. Methods: Approximately 130 adults (aged ≥18 years) will be allocated to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n = 40) must have previously treated unresectable or metastatic colorectal adenocarcinoma. Patients in cohort 2 (BTC; n = 40) must have previously treated locally advanced or metastatic BTC. Patients in cohort 3 (HCC; n ≤50) must have previously treated advanced HCC. Prior topoisomerase I inhibitor therapy is not allowed. Patients in cohorts 1 and 2 will receive patritumab deruxtecan intravenously (IV) as monotherapy. Cohort 3 includes a dose-escalation phase to determine the recommended phase 2 dose of patritumab deruxtecan monotherapy and an efficacy phase. In the efficacy phase, patients will receive the recommended phase 2 dose of patritumab deruxtecan. The primary objectives are to evaluate safety and tolerability of patritumab deruxtecan and to evaluate the confirmed objective response rate per RECIST v1.1 assessed by blinded independent central review (BICR) for each cohort. Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival, and to characterize the pharmacokinetics of patritumab deruxtecan. Clinical trial information: NCT06596694 .

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.

Relationship between androgen receptor and androgen receptor-related protein expression in breast cancers focusing on morphologically identified carcinoma with apocrine differentiation

Breast cancer (BC) is classified based on the expression of histopathological markers, namely, estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). Carcinomas with apocrine differentiation (CAD) are classified based on morphology. Androgen receptor (AR) is highly expressed in CAD; however, no study has comprehensively examined AR-related proteins in CAD. Therefore, we examined the expression of AR-related proteins and AR, compared protein expression patterns between morphologically identified CAD and other BC subtypes, and investigated CAD characteristics. We performed immunohistochemistry for AR and various AR-related proteins in 66 invasive ductal carcinoma (32 ER+/PgR+/HER2−, 8 ER+/PgR+/HER2+, 12 ER−/PgR−/HER2+, and 14 ER−/PgR−/HER2− [triple-negative breast cancer)), 21 invasive lobular carcinoma, and 27 CAD cases. In the CAD group, all cases were AR-positive; some AR-related proteins were highly expressed. Nuclear phosphorylated-mammalian target of rapamycin was highly expressed in CAD cases compared with that in other BC groups, with a 33.3% sensitivity and 97.7% specificity. AR-expressing CAD cases exhibited high expression of other AR-related proteins. Specifically, the combination of AR+, GCDFP15+, and ER − or AR+, FOXA1+, and ER − may be useful for the diagnosis and treatment of AR-positive BC and CAD. These results may assist in androgen-related molecular targeted therapy research.

Postoperative Radiotherapy ± Cetuximab for Intermediate-Risk Head and Neck Cancer.

Radiotherapy (RT)/cetuximab (C) demonstrated superiority over RT alone for locally advanced squamous head and neck cancer. We tested this in completely resected, intermediate-risk cancer. Patients had squamous cell carcinoma of the head and neck (SCCHN) of the oral cavity, oropharynx, or larynx, with one or more risk factors warranting postoperative RT. Patients were randomly assigned 1:1 to intensity-modulated RT (60-66 Gy) with once-per-week C or RT alone. The primary hypothesis was that RT + C would improve overall survival (OS) in randomly assigned/eligible patients, with a prespecified secondary plan to test this in the human papillomavirus (HPV)-negative subpopulation. Disease-free survival (DFS) and toxicity were secondary end points. OS and DFS were tested via stratified log-rank test; toxicity was compared via Fisher's exact test. We enrolled 702 patients from November 2009 to March 2018; 577 were randomly assigned/eligible. Most (63.6%) had oral cavity cancer and most (84.6%) had high epidermal growth factor receptor expression. There were fewer deaths (184) than expected. OS (median follow up, 7.2 years) was not significantly improved (hazard ratio [HR], 0.81; one-sided P = .0747; 5-year OS 76.5% v 68.7%), but DFS was (HR, 0.75; one-sided P = .0168; 5-year DFS 71.7% v 63.6%). Benefit of RT + C was only seen in the HPV-negative subpopulation (80.2% of patients in the trial). Grade 3-4 acute toxicity rates were 70.3% (RT + C) versus 39.7% (RT; two-sided P < .0001), mostly skin and/or mucosal effects. Late grade ≥3 toxicity rate was 33.2% (RT + C) versus 29.0% (RT; two-sided P = .3101). There were no grade 5 toxicities in either arm. RT + C significantly improved DFS, but not OS, with no increase in long-term toxicity, compared with RT alone for resected, intermediate-risk SCCHN. RT + C is an appropriate option for carefully selected patients with HPV-negative disease.

The mechanism underlying metastasis in triple-negative breast cancer: focusing on the interplay between ferroptosis, epithelial-mesenchymal transition, and non-coding RNAs

Triple-negative breast cancer (TNBC) is a type of breast cancer with lack the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is the most aggressive breast cancer and the most difficult to treat due to its poor response to treatments and extremely invasive characteristics. The typical treatment for TNBC frequently results in relapse because of the lack of particular treatment choices. It is urgent to focus on identifying a workable and effective target for the treatment of TNBC. Cancer metastasis is significantly influenced by epithelial-mesenchymal transition (EMT). Ferroptosis is an iron-dependent cell death form, and changes its key factor to affect the proliferation and metastasis of TNBC. Several reports have established associations between EMT and ferroptosis in TNBC metastasis. Furthermore, non-coding RNA (ncRNA), which has been previously described, can also control cancer cell death and metastasis. Thus, in this review, we summarize the correlation and pathways among the ferroptosis, EMT, and ncRNAs in TNBC metastasis. Also, aim to find out a novel strategy for TNBC treatment through the ncRNA-ferroptosis-EMT axis.

Cordycepin and Its Structural Derivatives Effectively Suppress the High Expression of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase in Breast Carcinomas: A Computational Drug Development Approach.

Breast cancer is a frequently diagnosed malignant disease and the primary cause of mortality among women with cancer worldwide. The therapy options are influenced by the molecular subtype due to the intricate nature of the condition, which consists of various subtypes. By focusing on the activation of receptors, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase can be utilized as an effective drug target for therapeutic purposes of breast cancer. The objective of this study is to compare the underlying pharmacological properties of several modified agents to the parental Cordycepin to target and inhibit the EGFR tyrosine kinase high expression, and to discover the inhibitor with the highest affinity for this drug target to treat the breast cancer patients. The Maestro Application of Schrödinger Suite Paid Software was initially employed for conducting extra precision (XP) structure-based virtual screening to evaluate the binding affinity of the Cordycepin and its 500 structural derivatives with the EGFR tyrosine kinase protein structure. In addition, the anti-breast cancer activity of the chosen compounds was assessed by looking at their drug-likeness and ADMET characteristics using Lipinski's rule of five along with Quantitative structure- activity relationship (QSAR) validation, the prediction of cell line anti-cancer, as well as anti- breast cancer activity of top docked scored compounds. Subsequently, the Desmond paid software- based molecular dynamics simulations (MDS) were conducted for a duration of 100 nanoseconds on the promising candidates followed by the binding free energy estimation was performed utilizing MM-GBSA analysis. To determine the stability of the protein-ligand complex, root-meansquare deviation (RMSD), root-mean-square fluctuation (RMSF), protein-ligand interactions, and other necessary parameters were evaluated from the 100 ns MDS Trajectory. Based on the overall analysis of our study, N (6)-octylamine adenosine (CID-194932) reported the optimum inhibitory potential against the EGFR tyrosine kinase protein, followed by Adenosine 5-monophosphate (CID-83862) and Cordycepin (CID-6303), which compared favorably to the control drug Vandetanib (CID-3081361). Consequently, these derivative compounds Cordycepin have the potential to be utilized as lead molecules in the development of highly effective and potent EGFR tyrosine kinase inhibitors for the treatment of breast cancer patients.

IL-22-mediated microRNA-124-3p/GRB2 axis regulates hyperproliferation and inflammatory response of keratinocytes in psoriasis.

Psoriasis is an inflammatory dermatosis that features overproliferation and inflammatory reaction of keratinocytes. A study reported that IL-22 is involved in the pathogenesis of psoriasis by mediating miR-124 to regulate the expression of fibroblast growth factor receptor 2 in keratinocytes. A microRNA may target multiple target genes. Therefore, we speculate that miR-124-3p may also target other downstream genes to affect IL -22-induced keratinocyte function. A possible target gene of miR-124-3p, growth factor receptor-bound protein 2 (GRB2), was screened by analyzing the target gene databases. GRB2 expression was elevated and miR-124-3p expression was decreased in psoriatic lesions compared to psoriatic adjacent normal skins and healthy controls. We performed the following cell experiments in the IL-22-stimulated HaCaT cell model. In keratinocytes transfected with the miR-124-3p mimics, GRB2 expression was significantly lower. We analyzed the regulation of keratinocyte proliferation by GRB2 and miR-124-3p. High levels of GRB2 promoted keratinocyte proliferation and expression of Ki67, PCNA, and K16, which were inhibited by low expression of GRB2. In addition, we found that the effect of GRB2 inhibitors on the proliferation and inflammatory response of keratinocytes was dose-dependent. Finally, we investigated the influence of GRB2 on inflammatory mediators in keratinocytes with the ELISA. After low expression of GRB2, the mRNA expression and secretion of the pro-inflammatory factor were suppressed. When both GRB2 and miR-124-3p were overexpressed, the cellular overproliferation and inflammation caused by GRB2 overexpression were significantly reversed by miR-124-3p. In summary, IL-22-mediated miR-124-3p regulates keratinocyte hyperproliferation and inflammatory response by suppressing GRB2 expression in psoriasis.

Circular RNA circAGAP1 promotes sunitinib sensitivity in renal cell carcinoma via sponging multiple PDGFR-targeted miRNAs.

Sunitinib resistance is a major challenge in advanced renal cell carcinoma (RCC). Clinically, elucidating the underlying mechanisms and developing practical countermeasures for sunitinib resistance in RCC is desirable. In previous studies, we found that circAGAP1 expression was significantly upregulated in clear cell RCC (ccRCC) and was strongly associated with poor prognosis. However, the role of circAGAP1 in sunitinib resistance in ccRCC remains unclear. We used public databases for bioinformatics analysis to identify the binding targets of circAGAP1. Additionally, the effects of circAGAP1 on the proliferation, clonogenesis, apoptosis, and migration of ccRCC cells were analyzed using quantitative real-time PCR, cell counting kit-8 assays, migration and apoptosis assays, and colony formation assays. Furthermore, RNA immunoprecipitation, dual-luciferase reporter, and fluorescence in situ hybridization assays were used to explore the molecular mechanism. In this study, circAGAP1 exhibited higher expression in sunitinib-sensitive ccRCC cells and inhibited the clonogenesis, proliferation, and migration of ccRCC cells after sunitinib treatment. Mechanical studies revealed that circAGAP1 regulated the expression of sunitinib target platelet-derived growth factor receptor by acting as a microRNA sponge that suppresses miR-149-5p, miR-455-5p, and miR-15a-5p simultaneously. Overexpression of these three miRNAs reversed circAGAP1-mediated sunitinib sensitivity in ccRCC. In summary, our findings indicate that circAGAP1 may serve as a promising biomarker to predict sunitinib sensibility and a therapeutic target in ccRCC.

Advancements in understanding the role and mechanism of sirtuin family (SIRT1-7) in breast cancer management.

Breast cancer (BC) is the most prevalent type of cancer in women worldwide and it is classified into a few distinct molecular subtypes based on the expression of growth factor and hormone receptors. Though significant progress has been achieved in the search for novel medications through traditional and advanced approaches, still we need more efficacious and reliable treatment options to treat different types and stages of BC. Sirtuins (SIRT1-7) a class III histone deacetylase play a major role in combating various cancers including BC. Studies reveal thateach sirtuin has a unique and well-balanced biology, indicating that it regulates a variety of biological processes that result in the initiation, progression,and metastasis of BC. SIRT also plays a major role in numerous vital biological functions, including apoptosis, axonal protection, transcriptional silencing, DNA recombination and repair, fat mobilization, and aging. As per the current demand, we wish to outline the structural insights into sirtuin's catalytic site, substantial variations among all SIRT types, and their mechanism in BC management. Additionally, this review will focus on the application of SIRT modulators along with their clinical significance, hurdles, and future perspective to develop successful SIRT-based drug candidates to conquer the BC problem.

Immunohistochemical Localization of Epidermal Growth Factor Receptor in Rat Buccal Mucosa Treated with Fenugreek Leaf Oil

The lack of effective treatment for oral mucosal ulcers has motivated clinicians to search for other therapeutic techniques to improve oral ulcer healing. Applying fenugreek to an ulcer triggers the release of its anti-inflammatory components, that might reduce any superfluous inflammatory processes and accelerate wound healing. The aim of this study was to investigate the effect of fenugreek leaf oil on the ulcer associated with the expression of epidermal growth factor receptor (EGFR). A total of 24 adult male rats weighing between 350 and 450 grams and 4-6 months of age were used in this study. The experimental design included: the normal group (no ulcer), the control group (12 ulcers left without treatment to the right), and the study group (12 ulcers on the left side were healed using fenugreek oil). All rats were sacrificed on the 3rd and 7th days of the experimental study, healing durations, and biological samples were prepared for histological and immunohistochemistry analysis of EGFR. The current study exhibited that the EGFR expression increased in ulcer sites treated with fenugreek after 3 days of ulceration with significant differences in comparison with other groups. In conclusion, fenugreek oil was efficient in promoting ulcer healing by enhancing epithelization. Moreover, the positive localization of EGFR increased in the study groups treated with fenugreek oil indicating its potential activity in accelerating the healing process‎‎‎.

Amiloride sensitizes prostate cancer cells to the reversible tyrosine kinase inhibitor lapatinib by modulating Erbb3 subcellular localization

Neoadjuvant therapy (NAT) has been studied in clinically localized prostate cancer (PCa) to improve the outcomes from radical prostatectomy (RP) by ‘debulking’ of high-risk PCa; however, using androgen deprivation therapy (ADT) at this point risks castration resistant PCa (CRPC) clonal proliferation. Our goal is to identify alternative NAT that reduce hormone sensitive PCa (HSPC) without affecting androgen receptor (AR) transcriptional activity. PCa is associated with increased expression and activation of the epidermal growth factor receptor (EGFR) family, including HER2 and ErbB3. The FDA-approved HER2 inhibitor lapatinib has been tested in PCa but was ineffective due to continued activation of ErbB3. We now demonstrate that this is due to ErbB3 being localized to the nucleus in HSPC and thus protected from lapatinib which affect membrane localized HER2/ErbB3 dimers. Here, we show that the well-established, well-tolerated potassium-sparing diuretic amiloride hydrochloride dose dependently prevented ErbB3 nuclear localization via formation of plasma membrane localized HER2/ErbB3 dimers. This in turn allowed lapatinib inactivation of these dimers via inhibition of its target HER2, which dephosphorylated ERK1/2 and inhibited survival. Amiloride combined with lapatinib significantly increased apoptosis at relatively low doses of both drugs but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with using ADT as NAT in HSPC.

Analysis of Estrogen Receptor Alpha (ERα) Expression and Epidermal Growth Factor Receptor (EGFR) Mutation and Their Relationship with Hormonal and Menstrual Factors in Women with Lung Adenocarcinoma

Lung cancer is the second most common cancer worldwide. The proportion of non-smoking women with lung cancer is higher than non-smoking men. Studies have found gender differences in estrogen receptor alpha expression and mutation in the human epidermal growth factor receptor in tumour tissue. The aim of the study is to analyze the expression of estrogen receptor alpha (ERα) and epidermal growth factor receptor (EGFR) in women with lung adenocarcinoma. The study is retrospective and includes 41 non-smoking women with lung adenocarcinoma. We studied the expression of ERα and EGFR mutations in tumour tissue and their relationship with the hormonal and menstrual factors. The positive expression of ERα in tumour tissue is 9.8%, and in these patients, the estradiol levels were many times higher. EGFR mutation expression is found in 26.8%. There is a correlation between the expression of the EGFR mutation and the time of menopause. The expression of ERα and EGFR in non-smoking women with lung adenocarcinoma is most likely related to the influence of sex hormones and menstrual factors.

Pericytes and Extracellular Vesicle Interactions in Neurovascular Adaptation to Chronic Arterial Hypertension.

Chronic arterial hypertension restructures the vascular architecture of the brain, leading to a series of pathological responses that culminate in cerebral small-vessel disease. Pericytes respond dynamically to vascular challenges; however, how they manifest under the continuous strain of hypertension has not been elucidated. In this study, we characterized pericyte behavior alongside hypertensive states in the spontaneously hypertensive stroke-prone rat model, focusing on their phenotypic and metabolic transformation. Flow cytometry was used to characterize pericytes by their expression of platelet-derived growth factor receptor β, neuroglial antigen 2, cluster of differentiation 13-alanyl aminopeptidase, and antigen Kiel 67. Microvessels were isolated for gene expression profiling and invitro pericyte expansion. Immunofluorescence validated the cell culture model. Plasma-derived extracellular vesicles from hypertensive rodents were applied as a treatment to assess their effects on pericyte function and detailed metabolic assessments on enriched pericytes measured oxidative phosphorylation and glycolysis. Our results reveal a shift in platelet-derived growth factor receptor β+ pericytes toward increased neuroglial antigen 2 and cluster of differentiation 13-alanyl aminopeptidase coexpression, indicative of their critical role in vascular stabilization and inflammatory responses within the hypertensive milieu. Significant alterations were found within key pathways including angiogenesis, blood-brain barrier integrity, hypoxia, and inflammation. Circulating extracellular vesicles from hypertensive rodents distinctly influenced pericyte mitochondrial function, evidencing their dual role as carriers of disease pathology and potential therapeutic agents. Furthermore, a shift toward glycolytic metabolism in hypertensive pericytes was confirmed, coupled with ATP production dysregulation. Our findings demonstrate that cerebral pericytes undergo phenotypic and metabolic reprogramming in response to hypertension, with hypertensive-derived plasma-derived extracellular vesicles impairing their mitochondrial function. Importantly, plasma-derived extracellular vesicles from normotensive controls restore this function, suggesting their potential as both therapeutic agents and precision biomarkers for hypertensive vascular complications. Further investigation into plasma-derived extracellular vesicle cargo is essential to further explore their therapeutic potential in vascular health.

Combining Water-Soluble Porphyrin and Phthalocyanine Photosensitizers With Doxorubicin Improves the Efficacy of Chemo-Photodynamic Therapy Against DMBA-Induced Breast Carcinoma.

Breast cancer ranks as the second most widespread form of cancer globally. Currently, combination therapy is being actively employed in clinical practice to augment the efficiency of anticancer treatment. Hence, the objective of this study was to assess the therapeutic efficacy of a combination of femtosecond laser-based photodynamic therapy (PDT) utilizing two distinct photosensitizers (PSs), zinc phthalocyanine tetrasulfonate (ZnPcS4) and α,β,χ,δ porphyrin-Tetrakis (1-methylpyridinium-4-yl) p-Toluenesulfonate porphyrin (TMPyP) in conjunction with doxorubicin chemotherapeutic agent, on mammary carcinomas experimentally induced in female mice using 7,12-dimethylbenz[a] anthracene (DMBA). Our results showed the efficiency of the combined therapy for promoting tissue apoptosis and necrosis as evidenced by histopathological observations and the noticeable reduction of Bcl-2 and Ki-67 expression. Moreover, there was a reduction in serum levels of the carcinoma antigen CA15-3 and transforming growth factor beta (TGF-β). Co-treatment of doxorubicin with ZnPcS4-PDT or TMPyP-PDT or a combination of both resulted in a decrease in the expression of epidermal growth factor receptor (EGFR) and its downstream oncogenes NRAS, NF-κB, mTERT, and c-Myc, and an increase in the expression of the caspase-3 apoptotic gene. These results validate the therapeutic potential of combining doxorubicin with PDT, highlighting the potential of this co-treatment strategy as a promising alternative for enhancing existing anticancer approaches.

15-Deoxy-Δ-12,14-Prostaglandin J2 Represses Immune Escape of Lung Adenocarcinoma by Polarizing Macrophages Through Epidermal Growth Factor Receptor/Ras/Raf Pathway.

Lung adenocarcinoma (LUAD) is a widespread and deadly form of cancer. Prostaglandin 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) possesses antioxidant, anti-inflammatory, and anticancer properties. However, it is unclear whether this effect on LUAD progression stems from its ability to influence macrophage polarization. By utilizing 3- (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, colony formation, transwell assays, and enzyme linked immunosorbent assay (ELISA), we investigated how 15d-PGJ2 affects A549 cell viability, proliferation, apoptosis, and invasion, as well as levels of interleukin (IL)-4, IL-13, and IL-17. Human monocytic cell line THP-1 was induced into M2 macrophages using phorbol 12-myristate 13-acetate and IL-4/IL-13, followed by treatment with 15d-PGJ2. The study employed flow cytometry to observe the polarization of macrophages, quantitative reverse transcription polymerase chain reaction (qRT-PCR) to identify epidermal growth factor receptor (EGFR) expression, western blot for identifying expression of macrophage marker proteins, and examining EGFR/rat sarcoma (Ras)/rapidly accelerated fibrosarcoma (Raf) activation. In a coculture setup, CD8+ T cells were shown to have a proliferation capacity by carboxifluorescein diacetate succinimidyl ester (CFSE), a killing ability by lactate dehydrogenase, and an analysis of their interferon gamma and tumor necrosis factor alpha levels by ELISA. 15d-PGJ2 reduced invasion capacity and expression of inflammatory cytokines, lowered A549 cell viability in a dose-dependent way, and promoted apoptosis. 15d-PGJ2 facilitated the transition of M2 macrophages to the M1 type, inhibited Ras/Raf pathway activation, reduced EGFR expression in macrophages, and stimulated CD8+ T cells to enhance anti-tumor immunity. 15d-PGJ2 repressed M2 macrophage polarization and LUAD immune evasion by targeting the EGFR/Ras/Raf pathway in macrophages.

FGF20 Secreted From Dermal Papilla Cells Regulate the Proliferation and Differentiation of Hair Follicle Stem Cells in Fine-Wool Sheep.

Wool traits determine the market value of fine-wool sheep, and wool fibre-breaking elongation (fibres can be stretched or elongated before they break) is one of the important wool traits. The interaction between hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) determines hair follicle development in fine wool sheep, thereby directly influencing wool traits. A genome-wide association study based on pre-sequencing data identified FGF20, which was significantly associated with wool fibre-breaking elongation. The study reveals that the regulatory mechanism of FGF20 secreted from DPCs affects the proliferation and differentiation of HFSCs through a co-culture system, to provide a new perspective for fine-wool sheep breeding. After knocking down FGF20 expression in DPCs, the results showed that the expression of fibroblast growth factor receptor 2 (FGFR2) and fibroblast growth factor receptor 3 (FGFR3) in DPCs and HFSCs was significantly decreased (p < 0.05), the number of EdU-positive cells and cell viability was significantly decreased (p < 0.01), and the apoptosis rate was significantly increased (p < 0.05). Meanwhile, the differentiation markers of SOX9, NOTCH1 and β-Catenin in HFSCs were also significantly reduced (p < 0.05). These findings indicate that FGF20-knockdown in DPCs of fine-wool sheep inhibits the proliferation and differentiation of HFSCs in the co-culture system, providing a theoretical basis for elucidating the regulatory mechanism of hair follicle self-renewal and differentiation of fine-wool sheep and providing a co-culture system for regenerative medicine.

Consumption of Endogenous Caspase-3 Activates Molecular Theranostic Nanoplatform against Inflammation-Induced Profibrotic Positive Feedback in Pulmonary Fibrosis.

The limited and backward diagnostic approaches elicit high mortality associated with pulmonary fibrosis (PF) because they fail to identify injury phase of PF. Developing a precisely theranostic nanoplatform presents a promising shortcut to reverse PF. Herein, a specific molecular nanotheranostic (Casp-GNMT), which is triggered by endogenous cysteinyl aspartate specific proteinase-3 (caspase-3), boosts antifibrotic efficacy through bioimaging synergistic with chemotherapy at molecular level, facilitating by ionizable lipid and reactive oxygen species sensitive lipid for precise and manageable therapy. The activation of molecular imaging probe (pCY-pairs) by consumption of endogenous caspase-3 initiates fluorescence resonance energy transfer-guided theranostic pattern, aiming to restore mitochondrial dysfunction-induced oxidative stress and inflammatory responses in alveolar epithelial cells II (AECs II). This process sequentially resists the expression of interleukin-1β and vascular endothelial growth factor receptor through combined with nintedanib, further suppressing abnormal injury of AECs II and persistent migration and proliferation of inflammatory cells. Especially, the homeostasis of injured AECs II diminishes excessive accumulation of transforming growth factor-β to restrain myofibroblasts proliferation and collagen deposition, thereby amplifying the possibility of reversing PF. This theranostic nanoplatform is proposed to provide a prompt and exact approach to enhance diagnostic authenticity and treating efficiency through harnessing endogenous indicator for PF reversal.

Mammographic parameters as predictors of molecular subtype of breast cancer: a prospective analysis

BackgroundThe prevalence of breast cancer is increasing globally and its early detection is the need of hour for giving the patient a long disease-free meaningful life. The latest management regimes depend upon the biological behavior of the breast cancer that itself relies upon expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her 2) neu status for its molecular subtyping.AimTo determine the predictive value of mammographic parameters in identifying the estrogen and progesterone hormone receptor status, human epidermal growth factor receptor 2 (Her 2) neu expression and molecular subtypes of breast cancer.MethodsA prospective observational study was conducted from January 2021 to September 2022 in a tertiary care institute. The study enrolled 51 females with histopathologically proven invasive breast carcinoma. The patients underwent digital mammography followed by tissue biopsy. Mammographic parameters were based on Breast Imaging-Reporting and Data System (BI-RADS) imaging features. The molecular subtypes of breast cancer were grouped into four subtypes based on St. Gallen International Expert Consensus Panel 2013. The mammographic features were then statistically correlated with molecular subtypes of breast cancer.ResultsLuminal type A was the most common molecular subtype in our study [ 17 (33.33%)] followed by triple negative type [10(19.61%)]. Tumors with non-circumscribed margins were predicted to be Luminal A or Luminal B subtype (p value < 0.02). Tumor with microcalcification was strongly predicted to be Her 2 subtype with a statistically significant association (p value < 0.001). Circumscribed tumors with absence of microcalcification were predicted to be triple-negative type of breast cancer.ConclusionsKey features in mammography were significantly associated with breast cancer molecular subtypes. Knowledge of such correlations could help clinicians stratify breast cancer patients according to their likely molecular subtypes, potentially enabling earlier, more effective treatment or aiding in therapeutic decisions in countries where immunohistochemical (IHC) hormone receptor and Her 2 testing is not readily available.

Synergistic inhibitory effect of atmospheric pressure plasma and berberine on non‑small cell lung cancer cells via inducing apoptosis.

Non-small cell lung cancer (NSCLC) is a type of lung cancer, the incidence and mortality rate have been high, and the use of monotherapy is easy to make patients develop tolerance. Atmospheric pressure plasma (APP) is an emerging technology for killing cancer cells in recent years, and combination of berberine (BBR) mechanism has not been fully elucidated for NSCLC. The article's primary goal is to investigate the effect of combination on NSCLC and its associated characterization. Antiproliferative effects were detected by cell viability assay and colony formation, and flow cytometry analysis of apoptosis and cycling showed that the combination synergistically induced apoptosis. Then, extracellular reactive oxygen species (ROS)levels and DCFH-DA-based kits examined intracellular ROS levels, and their effects on mitochondrial membrane potential were measured. Study reveals that co-induced apoptosis is associated with ROS accumulation. Subsequently, Western blotting (WB) detected the expression of epidermal growth factor receptor (EGFR), and the important signaling pathway proteins Ras/ERK and AKT/mTOR. Results showed that it could downregulation of EGFR protein expression and inhibit of activation of ERK/AKT signaling pathways. Simultaneous wound healing assay and epithelial-to-mesenchymal transition (EMT) marker detection were performed for the assessment of migration and EMT ability of NSCLC cells. Combination therapy inhibited migration and EMT of NSCLC cells. The results of this study show that the combination can synergistically induce apoptosis of NSCLC by regulating ROS production. EGFR downregulation and AKT/ERK signaling pathway inhibition are linked to the synergistic effect.

Discovery of a molecular glue for EGFR degradation.

Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.