Cicatrização de feridas diabéticas com fator de crescimento epidérmico: revisão integrativa / Healing of diabetic wounds with epidemic growth factor: integrative review / Curación de heridas diabéticas con factor de crecimiento epidérmico: revisión integrativa

Objetivo: Analisar as produções científicas sobre a efetividade do Fator de crescimento epitelial recombinante humano na cicatrização de feridas diabéticas. Métodos: Trata-se de uma revisão sistemática da literatura, a busca foi realizada nas bases de dados: Pubmed; Scopus e Lilacs. Resultados: Foram selecionados 21 artigos, sendo a maioria estudos experimentais (48%). A cicatrização completa de lesões tratadas com Fator de crescimento epitelial recombinante humano foi relatada por 17 artigos (81%). O aumento do tecido de granulação foi relatado em nove publicações (43%). Da mesma maneira, a diminuição da área da lesão foi descrita em dois artigos incluídos (10%). Duas publicações descrevem a diminuição do número de amputações e do estresse oxidativo e 62% dos artigos abordaram eventos adversos associados ao uso do produto (13/21), dos quais foram prioritários a ocorrência de tremores, dor local, calafrios, náuseas, infecção superficial, sensação de queimação e hematomas, considerados eventos adversos leves. Apenas um estudo apresentou a ocorrência de dor no peito como evento adverso grave. Conclusão: O fator de crescimento epitelial recombinante humano é indicado para uso tópico no tratamento de feridas diabéticas, evidenciando boa eficácia, porém mais estudos clínicos devem ser desenvolvidos. (AU)

Objective: To analyse the scientific studies of Human recombinant epithelial growth factor for the healing of diabetic wounds. Methods: A thorough review of the literature was performed in the following databases: PubMed, Scopus and LILACS. Results: 21 articles were selected, most studies were experimental (48%). Complete healing of Human recombinant epithelial growth factor-treated lesions has been reported by 17 articles (81%). Increased granulation tissue has been reported in nine publications (43%). Similarly, the reduction of the lesion area was described in two included articles (10%). Two publication describes the decrease in the number of amputations and oxidative stress and 62% of the articles addressed adverse events associated with the use of the product (13/21), of which the occurrence of tremors, local pain, chills, nausea, superficial infection, burning sensation and bruising were considered priority, considered adverse events light. Only one study showed chest pain as a serious adverse event. Conclusion: Although Human recombinant epithelial growth factor is indicated for topical use in the treatment of diabetic wounds and demonstrates good efficacy, more clinical studies should be developed. (AU)

Objetivo: Analizar la producción científica sobre la efectividad de Factor de crecimiento epitelial humano recombinante en la curación de heridas diabéticas. Métodos: Esta es una revisión sistemática de la literatura, la búsqueda se realizó en las bases de datos: Pubmed; Scopus y lilas. Resultados: Se seleccionaron 21 artículos. La mayoría de los estudios fueron experimentales (48%). 17 artículos informaron sobre la curación completa de lesiones tratadas con factor de crecimiento epitelial humano recombinante (81%). El aumento en el tejido de granulación se informó en nueve publicaciones (43%). Asimismo, se utilizó una reducción en el área de la lesión en dos artículos incluidos (10%). Dos publicaciones describen una disminución en el número de amputaciones y estrés oxidativo y el 62% de los artículos abordaron eventos adversos asociados con el uso del producto (13/21), que son las prioridades prioritarias en la aparición de temblores, dolor local, escalofríos, náuseas, infección superficial, sensación de ardor y hematomas, reflejos de eventos adversos leves. Solo un estudio muestra la aparición de dolor torácico como un evento adverso grave. Conclusión: Factor de crecimiento epitelial humano recombinante está indicado para uso tópico en el tratamiento de heridas diabéticas, mostrando buena eficacia, pero se deben desarrollar más estudios clínicos. (AU)

Asociación plaquetas-factor de crecimiento epidérmico en pacientes con cáncer pulmonar de células no pequeñas tratados con quimioterapia / Platelet-epidermal growth factor association in patients with non-small cell lung cancer treated with chemotherapy

RESUMEN Introducción: la concentración plasmática del factor de crecimiento epidérmico pudiera encontrarse alterada en pacientes con cáncer de pulmón de células no pequeñas y trombocitopenia/trombocitosis por quimioterapia. Objetivo: determinar la asociación existente entre la concentración plasmática plaquetaria y la concentración plasmática de factor de crecimiento epidérmico en pacientes con cáncer de pulmón de células no pequeñas tratados con quimioterapia, entre marzo de 2019 y febrero de 2020 en el Hospital Provincial Saturnino Lora. Métodos: se realizó un estudio observacional descriptivo transversal en el Hospital Provincial Saturnino Lora, provincia Santiago de Cuba, Cuba, entre marzo de 2019 y febrero de 2020. El universo estuvo constituido por 54 pacientes con diagnóstico de cáncer pulmonar de células no pequeñas tratados con quimioterapia. Por muestreo probabilístico aleatorio simple se seleccionó una muestra de 12 pacientes. Se midieron las variables: concentración plasmática plaquetaria (pre y post-quimioterapia), concentración plasmática de factor de crecimiento epidérmico (pre y post-quimioterapia), y modificación de la concentración plasmática de factor de crecimiento epidérmico (castración, no castración). Para el procesamiento de los datos se empleó el test estadístico T student y la correlación lineal de Pearson, así como la media y desviación estándar como medidas de resumen y dispersión, respectivamente. Resultados: entre las concentraciones plasmáticas plaquetaria y del factor de crecimiento epidérmico se halló una relación lineal de -0,37 previo a la quimioterapia y de -0,51, posterior a esta; no se encontraron diferencias estadísticamente significativas. Conclusiones: se concluye que la modificación de la concentración plasmática del factor de crecimiento epidérmico no guarda relación aparente con la modificación plasmática plaquetaria, con posible relación espuria, dada por la quimioterapia.

ABSTRACT Introduction: the plasma concentration of epidermal growth factor may be altered in patients with non-small cell lung cancer and thrombocytopenia/thrombocytosis due to chemotherapy. Objective: to determine the association between platelet plasma concentration and epidermal growth factor plasma concentration in patients with non-small cell lung cancer treated with chemotherapy between March 2019 and February 2020 at Saturnino Lora Provincial Hospital. Methods: a cross-sectional, descriptive and observational study was conducted at Saturnino Lora Provincial Hospital, Santiago de Cuba province, Cuba, between March 2019 and February 2020. The target group comprised 54 patients diagnosed with non-small cell lung cancer treated with chemotherapy. A sample of 12 patients was chosen by simple probability-random sampling: platelet plasma concentration (pre- and post-chemotherapy), epidermal growth factor plasma concentration (pre- and post-chemotherapy), and modification of epidermal growth factor plasma concentration (castration, non-castration) were measured. For data processing, the statistical T-student test and Pearson's linear correlation were applied, as well as the mean and standard deviation as summary and dispersion measures, respectively. Results: a linear relationship of -0.37 before chemotherapy and -0.51 after the chemotherapy was found between platelet and epidermal growth factor plasma concentrations; no statistically significant differences were found. Conclusions: it is concluded that the modification of the plasma concentration of epidermal growth factor has no apparent relationship with the platelet plasma modification, with possible spurious relationship, given by chemotherapy.

Pro-and Anti-inflammatory Biomarkers as Potential Prognosis Markers in Oral Squamous Cell Carcinoma

ABSTRACT: The most widely used method to classify prognostic factors in cancers today is TNM. However, Oral Squamous Cell Carcinoma (OSCC) often demonstrates different behaviors in relation to aggressiveness and therapeutic response at the same TNM stage. So, in such cases biomarkers can be used to identify the biological diversity of these tumors more reliably, leading to better therapeutic strategies and disease management. The presence of inflammatory immune cells in the tumor microenvironment can have pro or antitumor effects and the investigation of the expression of inflammatory markers in OSSC can be usefulto design immunotherapeutic interventions. The Transforming Growth Factor alpha is a potent stimulator of cell migration that acts on cell proliferation, invasion and metastasis of cancer, as well as immune suppression and angiogenesis. Inflammatory cytokines, such as Interferon-gamma, mediate macrophage differentiation. Macrophages are an important component of the OSCC microenvironment. The greater amount of tumor-associated macrophages, especially the M2 phenotype, may be associated with a more aggressive biological behavior of the OSCC and, consequently, with reduced survival.

RESUMEN: El método más utilizado para clasificar los factores de pronóstico en los cánceres en la actualidad es TNM. Sin embargo, el carcinoma oral de células escamosas (COCE) a menudo muestra diferentes comportamientos en relación con la agresividad y la respuesta terapéutica en la misma etapa TNM. Entonces, en tales casos, los biomarcadores pueden usarse para identificar la diversidad biológica de estos tumores de manera más confiable, lo que lleva a mejores estrategias terapéuticas y manejo de la enfermedad. La presencia de células inmunes inflamatorias en el microambiente tumoral puede tener efectos pro o antitumorales y la investigación de la expresión de marcadores inflamatorios en COCE puede ser útil para diseñar intervenciones inmunoterapéuticas. El factor de crecimiento transformante α es un potente estimulador de la migración celular que actúa sobre la proliferación celular, la invasión y metástasis del cáncer, así como la inmunosupresión y la angiogénesis. Las citocinas inflamatorias, como el IFN-γ, median en la diferenciación de macrófagos. Los macrófagos son un componente importante del microambiente COCE. La mayor cantidad de macrófagos asociados a tumores, especialmente el fenotipo M2, puede estar asociada a un comportamiento biológico más agresivo del COCE y, en consecuencia, a una menor supervivencia.

Estudo comparativo para avaliação da eficácia cicatrizante de formulações tópicas contendo Triticum aestivum L. (sinônimo Triticum vulgare) em modelo de pele humana nativa / Comparative study to evaluate the wound healing efficacy of topical formulations containing Triticum aestivum L. (Triticum vulgare) in a native human skin model

Introdução: extratos vegetais e ativos derivados de plantas tem sido desenvolvidos com o objetivo de melhorar e potencializar o processo de cicatrização cutânea, dentre eles, o Triticum aestivum L. (sinônimo Triticum vulgare). Objetivo: avaliar o efeito do extrato de grão inteiro (EGTA-PR) e extrato aquoso (EATA-FI) de Triticum aestivum L. na cicatrização cutânea em pele humana ex vivo. Métodos: fragmentos de pele obtidos de cirurgia plástica eletiva foram submetidos a lesões teciduais e tratados com os extratos durante oito dias para avaliação histológica da reepitelização e marcação proteica do fator de crescimento epidérmico (EGF). Resultados: EGTA-PR e EATA-FI aceleraram o processo de reepitelização em cultura de pele humana submetida a lesão tecidual. Adicionalmente, foi observado um aumento da marcação proteica de EGF após o tratamento com EGTA-PR. Conclusão: EGTA-PR apresentou um melhor desempenho na reepitelização quando comparado ao EATA-FI, pois apresentou uma maior marcação proteica para EGF em cultura de pele humana. Da mesma forma, os resultados histológicos mostraram que a redensificação dérmica obtida com o EGTA-PR foi visualmente superior à observada com EATA-FI. Os resultados obtidos são promissores e corroboram as diversas ações biológicas já reportadas na literatura para extrato de Triticum aestivum L. nas etapas da cicatrização tecidual.

Introduction: Plant extracts and actives derived from plants were developed to improve and enhance the skin healing process including Triticum aestivum L. (Triticum vulgare). Purpose: To evaluate the effect of whole grain extract (EGTA-PR) and aqueous extract (EATA-FI) of Triticum aestivum L., on ex vivo skin healing. Methods: Skin fragments obtained from elective plastic surgery were subjected to tissue damage and treated with extracts for eight days for histological evaluation of re-epithelialization and immunofluorescence for epidermal growth factor (EGF). Results: EGTA-PR and EATA-FI accelerated the re-epithelialization process in human skin culture submitted to tissue injury. Additionally, we observed increased EGF protein labeling after treatment with EGTA-PR. Conclusion: EGTA-PR showed a better performance in re-epithelialization when compared to EATA-FI, as it presented a higher protein labeling for EGF in human skin culture. Likewise, the histological results showed that the dermal redensification obtained with EGTA-PR was visually superior to that observed with EATA-FI. The results obtained are promising and corroborate the several biological actions already reported in the literature for Triticum aestivum L. extract in tissue healing stages

Anti-tumor activity of novel targeting HER2 antibody-drug conjugates / 药学学报

Antibody-drug conjugates (ADCs) are widely used in cancer treatment. Human epidermal growth factor receptor-2 (HER2) is overexpressed in various types of solid tumors and is a validated therapeutic target for cancers. To develop a more effective therapy, we generated a novel anti-HER2 humanized monoclonal antibody MIL40 and MIL40 drug conjugates as novel cancer therapies. The MIL40 was conjugated with small molecule cytotoxic agents DM1 [emtansine, N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] or monomethylauristatin E (MMAE) to generate ADCs, which were evaluated for their in vitro and in vivo anti-cancer activities. Experimental results show that MIL40-DM1 and MIL40-MMAE can effectively identify and bind to HER2-positive tumor cells. The binding capabilities of MIL40-DM1 and MIL40-MMAE with HER2 extracellular domain (ECD) antigens were not different after conjugation with DM1 or MMAE. The ADCs showed potent cytotoxicity in HER2-positive ovarian cancer cells SKOV3, breast cancer cells SKBR3 and stomach cancer cells N87 in vitro. MIL40-DM1 can effectively inhibit the volume and weight growth of SKOV3 transplant tumors in mice. The mice in this study were used and treated by following the international guidelines for the care and use of laboratory animals, and approved by Animal Ethics Committee of Institute of Military Cognitive and Brain Sciences.

Progress of epidermal growth factor in breast milk / 国际儿科学杂志

Breastfeeding plays a crucial role in the early and even later health of offspring.Epidermal growth factor(EGF)in breast milk is one of growth factor family members, which can regulate energy balance and is closely related to the growth and development of infants.In recent years, researchers at home and abroad have paid close attention to the research of EGF in breast milk.The paper summarizes the basic situation of EGF, and the content, the influencing factors, the main functions of EGF in breast milk and the risk relationship between EGF in breast milk and diseases, in order to point out the direction for further research of EGF in breast milk.

Pharmacoeconomic evaluation of pyrotinib combined with capecitabine in the second-line treatment of HER- 2 positive patients with advanced breast cancer / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of pyrotinib combined with capecitabine in the second-line treatment of human epidermal growth factor receptor- 2（HER-2）positive advanced breast cancer from the point of view of medical and health system ，and to provide reference for the selection of clinical therapy plan and national health decision. METHODS The dynamic Markov model was constructed on the basis of a multicenter ，open，randomized controlled phase Ⅲ clinical trial in 29 centers in China. The simulation time limit was 8 years，and the cycle was 21 days. The cost-effectiveness of pyrotinib combined with capecitabine （observation group ）were compared with that of lapatinib combined with capecitabine （control group ）in the second-line treatment of HER- 2 positive advanced breast cancer. The incremental cost-utility ratio （ICER）was calculated by using quality-adjusted life year （QALY）as output indicators ，and the sensitivity analysis was carried out to validate the robustness of the results of basic analysis. RESULTS The results of basic analysis showed that compared with control group ，the incremental cost per capita and incremental utility per capita of observation group were 67 953.82 yuan and 0.40 QALYs；ICER was 168 861.89 yuan/QALY，which was lower than the willing to pay （WTP）threshold（217 500 yuan/QALY）represented by 3 times of China ’s per capita GDP in 2020，indicating the treatment plan of the observation group is more cost-effective. The results of single factor sensitivity analysis showed that the proportion of patients treated with trastuzumab or pyrotinib after entering disease progression （PD）status in the control group ，the proportion of patients treated with lapatinib or trastuzumab after entering PD status in the observation group ，the cost of capecitabine and other parameters showed great impact on ICER ，but those parameters didn ’t cause the reverse of basis analysis results. The results of probabilistic sensitivity analysis showed that when the WTP threshold was 217 500 yuan/QALY，the probability that the treatment plan in the observation group was cost-effective was 94.10％. The results of partition survival model analysis were consistent with those of dynamic Markov model. CONCLUSIONS On the premise of taking 3 times of China ’s per capita GDP in 2020 as the WTP lin- threshold， the second-line treatment of HER- 2 positive wang9805@163.com advanced breast cancer with pyrotinib combined with capecitabine is more cost-effective than that with lapatinib combined with capecitabine.

Antitumor activity of a novel HER3-targeting antibody-drug-conjugate / 药学学报

As a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases, HER3 is an aberrantly activator of the PI3K/AKT pathway. Studies have indicated that HER3 is related to the progression of a variety of tumor types such as breast cancer, non-small cell lung cancer (NSCLC), ovary cancer and colon cancer, and in acquired resistance to EGFR and HER2 therapies. However, the attempts to target HER3 with neutralizing antibodies are not ideal previously. This is most likely due to the fact that the antibodies targeting HER3 fail to completely block the heterodimerization of HER3 and other receptors. Antibody-drug conjugates (ADCs) can specifically bind to target cells and exert the highly cytotoxicity effect on cancer cells through chemical drugs. ADCs have been widely used in clinical cancer therapies. We analyzed and optimized the structure of the antigen-antibody complex between HER3 and antibody LmAb3 by computer-aided molecular simulation technology, and the key sites involved in antigen binding in LmAb3 were predicted by distance geometry and computer graphics technology. Then a novel anti-HER3 antibody FD001 was obtained by point mutation technology. The affinity measurement by ForteBio results showed that the affinity of FD001 is much higher than LmAb3, the KD values of FD001 and LmAb3 with HER3 were 1.48E-11 and 2.46E-10, respectively. Antibody drug conjugate FD001-DM1 is obtained by coupling FD001 to DM1 [emtansine, N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] by lysine coupling technology. The results of cell cytotoxicity experiments showed that FD001-DM1 could effectively inhibit the proliferation of HER3-positive HT-29 colon cancer cells, with EC50 value of 33.62 nmol·L-1. The in vivo xenografts therapy results showed that the tumor volume of the FD001-DM1 treatment group was about 25% of that of the control group, and there was no significant weight reduction of the mice. These results reveal that FD001-DM1 had good in vivo and in vitro anti-tumor activity with high safety, which may provide effective help for further exploration of HER3-targeted ADCs drugs. The mice in this study were used and treated in accordance with international laboratory animal care and use guidelines and approved by the Animal Ethics Committee of the Military Cognitive and Brain Science Institute of the Military Medical Research Institute.

Emerging role of natural products in cancer immunotherapy

Cancer immunotherapy has become a new generation of anti-tumor treatment, but its indications still focus on several types of tumors that are sensitive to the immune system. Therefore, effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy. Natural products are reported to have this effect on cancer immunotherapy, including cancer vaccines, immune-check points inhibitors, and adoptive immune-cells therapy. And the mechanism of that is mainly attributed to the remodeling of the tumor-immunosuppressive microenvironment, which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy. Therefore, this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism. And we found that saponins, polysaccharides, and flavonoids are mainly three categories of natural products, which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment. Besides, this review also collected the studies about nano-technology used to improve the disadvantages of natural products. All of these studies showed the great potential of natural products in cancer immunotherapy.

Peroxidase from foxtail millet bran exerts anti-colorectal cancer activity via targeting cell-surface GRP78 to inactivate STAT3 pathway

Molecular targeted therapy has become an emerging promising strategy in cancer treatment, and screening the agents targeting at cancer cell specific targets is very desirable for cancer treatment. Our previous study firstly found that a secretory peroxidase of class III derived from foxtail millet bran (FMBP) exhibited excellent targeting anti-colorectal cancer (CRC) activity in vivo and in vitro, whereas its underlying target remains unclear. The highlight of present study focuses on the finding that cell surface glucose-regulated protein 78 (csGRP78) abnormally located on CRC is positively correlated with the anti-CRC effects of FMBP, indicating it serves as a potential target of FMBP against CRC. Further, we demonstrated that the combination of FMBP with the nucleotide binding domain (NBD) of csGRP78 interfered with the downstream activation of signal transducer and activator of transcription 3 (STAT3) in CRC cells, thus promoting the intracellular accumulation of reactive oxygen species (ROS) and cell grown inhibition. These phenomena were further confirmed in nude mice tumor model. Collectively, our study highlights csGRP78 acts as an underlying target of FMBP against CRC, uncovering the clinical potential of FMBP as a targeted agent for CRC in the future.

Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice

Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.

Research progress of EGFRvIII targeted immunotherapy in the treatment of glioblastoma / 药学学报

Glioblastoma (GBM) is the most common primary brain tumor, which is prone to recurrence and metastasis with poor prognosis. In recent years, immunotherapy has prolonged the survival of patients with GBM, providing a new option for the treatment of GBM. Target selection is very important for immunotherapy. Epidermal growth factor receptor variant III (EGFRvIII) is highly expressed on the surface of GBM cells in some patients, and EGFRvIII was not expressed in normal tissues. EGFRvIII are pivotal for the occurrence and progression of GBM, various targeted therapy including immunotherapy is promising to improve the efficacy of GBM. Currently, there are various approaches to target EGFRvIII, including humanized monoclonal antibodies, adoptive cell therapies and therapeutic vaccines. In this review, we focus on the preclinical and clinical findings of targeting EGFRvIII for GBM.

A review: drug-drug interactions of epithelial growth factor receptor-tyrosine kinase inhibitors / 中华肿瘤杂志

Mutations in the epithelial growth factor receptor (EGFR) is a driving factor that causes non-small cell lung carcinoma (NSCLC). The epithelial growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a crucial discovery in the treatment of lung cancer, particularly the efficacy of EGFR-TKIs is superior to that of the standard chemotherapy for patients with EGFR mutation-positive advanced NSCLC. Patients with NSCLC use EGFR-TKIs and other medications simultaneously is commonly seen, especially among those with comorbidities, which increases the risk of drug-drug interactions (DDIs) of EGFR-TKIs. The most common mechanisms underlying the DDIs of EGFR-TKIs are modulations of cytochrome P450 (CYP) and drug transporters [including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)], as well as gastrointestinal acid-inhibitory drugs [proton pump inhibitors (PPIs) and H(2) receptor antagonists (H(2)RA)]. Inhibitors or inducers of CYP enzymes and drug transporters can inhibit or accelerate the metabolism of EGFR-TKIs, which increase or reduce the exposure of EGFR-TKIs, thereby affect the efficacy and safety of EGFR-TKIs. In addition, PPIs or H(2)RA can decrease the solubility, bioavailability and efficacy of EGFR-TKIs. This review summarizes the mechanisms of DDIs of gefitinib, erlotinib, icotinib, afatinib, dacomitinib and osimertinib; the management recommendations for DDIs of those EGFR-TKIs from the Chinese and global guideline, as well as from the recent pre-clinical and clinical studies, which provide the reference and evidence for managing the combination therapies of EGFR-TKIs and other medications in clinics.

Effect of Guiqi Baizhu Prescription Combined with Oxaliplatin on Expression of EGFR and VEGFR2 and Angiogenesis in Gastric Cancer-bearing Mice / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Guiqi Baizhu prescription （GQBZ） combined with oxaliplatin on the expression of epidermal growth factor receptor （EGFR） and vascular endothelial growth factor receptor-2 （VEGFR2） and angiogenesis in gastric cancer-bearing mice. MethodThe tumor-bearing model of gastric cancer was induced in Kunming mice. The mice were randomly divided into blank group， model group， oxaliplatin group （10 mg·kg-1）， and high- （17.68 g·kg-1）， medium- （8.84 g·kg-1）， and low-dose （4.42 g·kg-1） combination groups （GQBZ combined with oxaliplatin）. After the last administration， the transplanted tumor was collected and the tumor inhibition rate was calculated. Hematoxylin-eosin （HE） staining was used to observe the morphological changes of tumor tissues. Enzyme-linked immunosorbent assay （ELISA） was used to detect the serum content of epidermal growth factor （EGF）， interleukin-8 （IL-8）， and vascular endothelial growth factor （VEGF）. Western blot and immunohistochemistry （IHC） were used to detect the expression of EGFR， phosphorylated EGFR （p-EGFR）， VEGFR2， phosphorylated VEGFR2 （p-VEGFR2）， and platelet-endothelial cell adhesion molecule （CD31）. Real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of EGFR and VEGFR2. ResultThe tumor weight in the drug intervention groups was significantly lower than that in the model group （P<0.01）. Compared with the oxaliplatin group， the high- and medium-dose combination groups showed reduced tumor weight （P<0.05， P<0.01）. The tumor cells in the model groups were high in cell density and regular in shape， and no clear tissue necrosis was seen. The tumor cell density in the drug intervention groups was reduced， and clear tissue necrosis and large-scale inflammatory cells were visible. Compared with the blank group， the model group and the drug intervention groups showed increased serum levels of EGF， VEGF， and IL-8 （P<0.05， P<0.01）. Compared with the model group， the drug intervention groups showed decreased serum levels of EGF， VEGF， and IL-8 （P<0.01）， reduced protein expression of EGFR， p-EGFR， VEGFR2， p-VEGFR2， and CD31， and declining mRNA expression of EGFR and VEGFR （P<0.01）. Compared with the oxaliplatin group， the high- and medium-dose combination groups showed decreased serum levels of EGF， VEGF， and IL-8 （P<0.05， P<0.01）， reduced protein expression of EGFR， p-EGFR， VEGFR2， p-VEGFR2， and CD31， and dwindled mRNA expression of EGFR and VEGFR2 （P<0.05， P<0.01）. The low-dose combination group showed decreased serum levels of EGF， VEGF， and IL-8， reduced protein expression of EGFR， p-EGFR， VEGFR2， p-VEGFR2， and CD31， and dwindled mRNA expression of EGFR and VEGFR2， but the difference was not statistically significant. ConclusionGQBZ combined with oxaliplatin can inhibit the growth and angiogenesis of tumor tissues in gastric cancer-bearing mice by affecting the expression of EGFR and VEGFR2.

Effect of Maxing Shigantang on Airway Injury and EGFR Expression in Asthma Model Rats / 中国实验方剂学杂志

ObjectiveTo explore the optimal formula of Maxing Shigantang in regulating epidermal growth factor receptor（EGFR）expression and alleviating airway injury in asthmatic rats and to reveal the underlying mechanism. MethodSD male rats were randomly divided into normal group, model group, dexamethasone group (5×10-4 g·kg-1) and Maxing Shigantang 1∶0.5, 1∶1, 1∶2 groups (group A, B, C, 10 g·kg-1), with 8 rats in each group. The other groups except the normal group received nebulization of 2% acetylcholine chloride and 0.4% histamine phosphate for the modeling of asthma. One hour before modeling， the normal group and the model group were given the same amount of normal saline， and the other groups were given the same amount of corresponding drugs， once a day for 7 days. On the 7th day， the model was established and the incubation period of asthma was recorded. The rats were then immediately anesthetized， and arterial blood and tracheal tissue were collected. Enzyme-linked immunosorbent assay （ELISA） was employed to detect the levels of interleukin-2 （IL-2）， interleukin-4 （IL-4）， and tumor necrosis factor-α （TNF-α） in serum. Pathological sections were prepared for the observation of the pathological changes of tracheal tissues and the ultrastructure of epithelial cells in each group. Terminal-deoxynucleotidyl transferase-mediated nick-end labeling （TUNEL） was adopted to detect epithelial cell apoptosis， and in situ hybridization and Western blot were employed to determine the mRNA and protein levels of epidermal growth factor receptor （EGFR）， respectively. ResultCompared with the model group， groups A， B and C prolonged the incubation period of asthma （P<0.05，P<0.01）. Compared with the control group， the model group showed declined IL-2 level （P<0.01）， risen IL-4 and TNF-α levels （P<0.05，P<0.01）， increased airway pathology score， collagen volume fraction， and airway epithelial cell apoptosis index （P<0.01）， and up-regulated mRNA and protein levels of EGFR in trachea tissue （P<0.01）. Compared with the model group， group A showed increased IL-2 level （P<0.05） and declined IL-4 （P<0.05，P<0.01） level， and group B showed declined IL-4 level （P<0.05）. The level of TNF-α in groups A， B， and C declined compared with that in the model group （P<0.01）. Maxing Shigantang repaired the tracheal tissue to different degrees （P<0.05）. Among the three groups， group A inhibited tracheal fibrosis （P<0.05） and had the most significant effect of repairing the ultrastructural changes of airway epithelial cells. Groups A， B and C all inhibited the apoptosis of airway epithelial cells （P<0.05）. All the three groups inhibited the up-regulation of EGFR mRNA level （P<0.05，P<0.01）， and groups B and C inhibited the up-regulation of EGFR protein level （P<0.05，P<0.01）. ConclusionMaxing Shigantang can inhibit the abnormal changes of airway epithelial structure， alleviate airway injury， and can down-regulate the expression of EGFR in the tracheal tissue of asthma model rats. In this study， the optimal compatibility of Maxing Shigantang to repair airway epithelial injury in asthmatic rats was group A， with the Ephedrae Herba-Armeniacae Semen Amarum-Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum ratio of 1∶0.5∶4∶1.

Progress of osimertinib in epidermal growth factor receptor mutant non-small cell lung cancer / 肿瘤研究与临床

As an important tumor driver gene, epidermal growth factor receptor (EGFR) gene plays an important role in the development and progression of non-small cell lung cancer (NSCLC). As the latest generation of EGFR-tyrosine kinase inhibitor (TKI) drugs, osimertinib has brought significant therapeutic efficacies and encouraging results both in patients with sensitive EGFR mutations and patients with rare EGFR mutations. Compared with previous EGFR-TKI drugs, osimertinib has strong blood-brain barrier penetration, which can effectively prevent the occurrence of lung cancer brain metastasis. After the resistance of first and second generation of targeted drugs, osimertinib is still effective in the follow-up treatment process. This article reviews the characteristics of EGFR mutation, the action mechanism of osimertinib, and the latest progress of osimertinib in treatment of EGFR mutations in NSCLC.

Mutations of epidermal growth factor receptor gene in non-small cell lung cancer patients and the correlation with clinical characteristics and therapeutic effects / 肿瘤研究与临床

Objective:To investigate the clinical characteristics of non-small cell lung cancer (NSCLC) patients with different epidermal growth factor receptor (EGFR) gene mutations and the comparison of therapeutic effects.Methods:The clinical data of 324 patients with NSCLC admitted to the 904th Hospital of the Joint Service Support Force of PLA from April 2018 to June 2020 were retrospectively analyzed. Gene sequencing method was used to detect EGFR gene and mutations of exons 19 and 21. NSCLC patients with EGFR gene mutations were divided into group A (mutation of exon 19 of EGFR gene) and group B (mutation of exon 21 of EGFR gene). Both groups were treated with gefitinib combined with TP (paclitaxel + cisplatin) regimen for 3 months. The clinical features, efficacy and adverse reactions of the two groups were compared.Results:Among 234 NSCLC patients, 107 cases (45.73%) had EGFR gene mutations. Among them, there were 49 cases in group A (including delE746-A750 mutation in 32 cases, delL747-P753insS 3 mutation in 8 cases, delL747-A750 1 mutation in 6 cases, delL747-T751 1 mutation in 3 cases), and there were 58 cases in group B (all L858R mutations), and no double mutations in exons 19 and 21 were found in both groups. There were no significant differences in gender, TNM staging, pathological type, smoking history, age, degree of differentiation, tumor location, tumor diameter, and lymph node metastasis in the two groups (all P > 0.05). The difference in the clinical control rates of group A and group B was not statistically significant [91.8% (45/49) vs. 89.7% (52/58), χ2=0.15, P = 0.699]. The incidence of grade Ⅲ-Ⅳ adverse reactions in the two groups during treatment had no statistically significant differences (all P > 0.05). Conclusions:EGFR mutation rate in NSCLC patients is relatively high, most of which are EGFR exons 19 and 21 mutations. Gefitinib combined with TP regimen in the treatment of EGFR exons 19 and 21 mutations in NSCLC patients has good curative effects and high safety.

EGFR mutation, expression of PD-L1/Ki-67 and their correlation with clinical features in elderly NSCLC patients / 中华检验医学杂志

Objective:To investigate the mutation of epidermal growth factor receptor (EGFR), the expression of programmed death ligand 1 (PD-L1), cell proliferation-associated antigen (Ki-67) in elderly patients with non-small cell lung cancer (NSCLC), and their correlation with clinical feature such as gender, histological type and TNM stage.Methods:The tissue samples of 340 elderly NSCLC patients with definite histopathological diagnosis were collected from January 2020 to December 2020 in Huadong Hospital Affiliated to Fudan University, including 195 males and 145 females, age between 68.9±6.0 years. Patients were grouped according to clinical features such as gender, histological type and TNM stage. The expression of EGFR mutation, PD-L1 and Ki-67 were detected by Super-ARMS and immunohistochemistry. The correlation between tnem and clinical features was statistically analyzed, and the correlation between EGFR mutation and PD-L1/Ki-67 expression was further analyzed separately.Results:In elderly NSCLC patients′ tissues, the positive rate of EGFR mutation was 48.53% (165/340). L858R and 19del mutations were the most common types, which were 56.36% (93/165), 30.30% (50/165) respectively. The mutation rate of EGFR was higher in women, lung adenocarcinoma, well-differentiated, and low-stage patients, which were 65.52% (95/145), 53.77% (164/305), 56.75% (143/252), 52.53% (135/257) respectively. In addition, the positive rate of PD-L1 expression was higher in elderly patients with non-adenocarcinoma lung cancer and poorly differentiated adenocarcinoma, which were 37.14% (13/35), 24.53% (13/53) respectively. The negative rate of PD-L1 expression was higher in elderly patients with NSCLC in stage Ⅰ+Ⅱ, no lymph node metastasis and weakly positive Ki-67, which were 89.11% (229/257), 87.63% (248/283), 94.71% (197/208) respectively. Correlation analysis showed that EGFR mutation was negatively correlated with the expression of PD-L1 and Ki-67 (PD-L1: r=-0.22, P<0.001; Ki-67: r=-0.32, P<0.001). Conclusion:There is a negatively correlation between EGFR mutation and the expression of PD-L1 and Ki-67 in elderly NSCLC, suggesting that the combined detection of EGFR mutation and PD-L1 expression could provide the basis for precise targeted therapy for elderly NSCLC patients.

In vitro effect of a short hairpin RNA targeting epidermal growth factor receptor combined with sirolimus on proliferation and apoptosis of the human cutaneous squamous cell carcinoma cell line Colo-16 / 中华皮肤科杂志

Objective:To investigate the effect of a short hairpin RNA (shRNA) targeting epidermal growth factor receptor (EGFR) combined with sirolimus on proliferation and apoptosis of the human cutaneous squamous cell carcinoma cell line Colo-16, and to explore underlying mechanisms.Methods:Cultured Colo-16 cells were divided into 5 groups: normal cell group receiving conventional culture and treatment with phosphate-buffered saline (PBS) , negative control group transfected with a shRNA-NC-expressing plasmid and treated with PBS, sirolimus group receiving conventional culture and sirolimus treatment, EGFR shRNA group transfected with an EGFR shRNA-expressing plasmid and treated with PBS, and combined group transfected with an EGFR shRNA-expressing plasmid and treated with sirolimus. Methyl thiazol tetrazolium (MTT) assay was performed to evaluate cellular proliferative activity in the above groups from 24 to 96 hours, and flow cytometry to detect cell apoptosis after 48-hour treatment. Semiquantitative RT-PCR was conducted to determine the mRNA expression of Bcl-2 and Bax, and Western blot analysis to determine the expression of apoptosis-related proteins cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, cell proliferation-related proteins phosphorylated mammalian target of rapamycin (p-mTOR) , phosphorylated protein kinase B (p-AKT) , phosphorylated 70-kDa ribosomal protein S6 kinase (p-P70S6k) , and cyclin D1. Comparisons among groups were carried out by using one-way analysis of variance, and multiple comparisons between 2 groups by using Student-Newman-Keuls q test. Results:MTT assay showed that the proliferative activity of Colo-16 cells was significantly lower in the sirolimus group, EGFR shRNA group and combined group during 24 - 96 hours than in the normal cell group (all P < 0.05) , and higher in the combined group than in the sirolimus group and EGFR shRNA group at 24-96 hours (all P < 0.001) , and there was no significant difference in the cellular proliferative activity at any time points between the normal cell group and negative control group (all P > 0.05) . Flow cytometry showed that the apoptosis rate was significantly higher in the sirolimus group, EGFR shRNA group and combined group (9.52% ± 0.25%, 12.65% ± 0.23%, 19.81% ± 0.31%, respectively) than in the normal cell group (3.33% ± 0.18%, q = 60.07, 78.08, 122.81, respectively, all P < 0.001) and negative control group (3.42% ± 0.19%, q = 59.90, 77.91, 122.64, respectively, all P < 0.001) , and was highest in the combined group. As RT-PCR and Western blot analysis revealed, the sirolimus group, EGFR shRNA group and combined group showed significantly decreased mRNA expression of Bcl-2 and protein expression of cyclin D1, p-AKT, p-mTOR, p-P70S6K and Bcl-2, but significantly increased mRNA expression of Bax and protein expression of cleaved caspase-3, cleaved caspase-9 and Bax compared with the normal cell group (all P < 0.05) . Compared with the sirolimus group and EGFR shRNA group, the combined group showed significantly decreased mRNA expression of Bcl-2 and protein expression of cyclin D1, p-AKT, p-mTOR, p-P70S6K and Bcl-2 (all P < 0.05) , but significantly increased mRNA expression of Bax and protein expression of cleaved caspase-3, cleaved caspase-9 and Bax (all P < 0.01) . Conclusion:EGFR shRNA and sirolimus exerted a synergistic effect in inhibiting the proliferation and promoting the apoptosis of Colo-16 cells, which may be related to the inhibition of the phosphoinositide 3-kinase (PI3K) /AKT/mTOR pathway.

Role of epidermal growth factor in repair of lung tissues in mice with acute respiratory distress syndrome / 中华麻醉学杂志

Objective:To evaluate the role of epidermal growth factor (EGF) in repair of lung tissues in mice with acute respiratory distress syndrome (ARDS).Methods:Fifty SPF male C57BL/6 mice, aged 6-8 weeks, weighing 21-23 g, were divided into 5 groups ( n=10 each) using a random number table method: control group (group C), EGF group, LPS+ PBS group, LPS+ EGF group and AG1478+ LPS+ EGF group.PBS 0.1 ml was intraperitoneally injected in group C. EGF 10 μg (0.1 ml) was intraperitoneally injected in group EGF.The equal volume of PBS and EGF 10 μg was intraperitoneally injected at 12 h after tracheal infusion of LPS in group LPS+ PBS and group LPS+ EGF, respectively.EGF receptor (EGFR) antagonist AG1478 1 mg was intraperitoneally injected, 30 min later LPS was tracheally instilled, and 12 h later EGF 10 μg was intraperitoneally injected in group AG1478+ LPS+ EGF.ARDS model was developed by endotracheal instillation of LPS 3 mg/kg.The mice were sacrificed on the 1st and 5th days after development of the model, and lung tissues were obtained for microscopic examination of the pathological changes which were scored after HE staining.Bronchoalveolar lavage was performed on 5th day after development of the model and before sacrifice, and bronchoalveolar lavage fluid (BALF) was collected to detect total protein concentration (by BCA method) and IL-6 and TNF-α concentrations (by enzyme-linked immunosorbent assay). Lung tissues were obtained for determination of the wet/dry lung weight ratio (W/D ratio), expression of lung surfactant associated protein C (SP-C) and proliferating nuclear antigen (PCNA) (by immunofluorescence method), and expression of EGFR, phosphorylated EGFR (p-EGFR), protein kinase B (Akt), and phosphorylated Akt (p-Akt) (by Western blot). Results:Compared with group C, the pathological score, W/D ratio, concentrations of total protein, IL-6 and TNF-α in BALF and neutrophil count were significantly increased, the number of cells co-expressing SP-C and PCNA was increased, and p-EGFR/EGFR and p-Akt/Akt ratios were increased in group LPS+ PBS ( P<0.01), and no significant change was found in the indexes mentioned above in group EGF ( P>0.05). Compared with group LPS+ PBS, the pathological score, W/D ratio, concentrations of total protein, IL-6 and TNF-α in BALF and neutrophil count were significantly decreased, the number of cells co-expressing SP-C and PCNA was increased, and p-EGFR/EGFR and p-Akt/Akt ratios were increased in group LPS+ EGF ( P<0.01). Compared with group LPS+ EGF, the pathological score, W/D ratio, concentrations of total protein, IL-6 and TNF-α in BALF and neutrophil count were significantly increased, the number of cells co-expressing SP-C and PCNA was decreased, and p-EGFR/EGFR and p-Akt/Akt ratios were decreased in group AG1478+ LPS+ EGF ( P<0.01). Conclusions:EGF can promote the repair of lung tissues in mice with ARDS, and the mechanism may be related to activation of EGFR signaling pathway and promotion of proliferation of alveolar epithelial cell type Ⅱ.