Clinical application and progression of monoclonal antibodies targeting HER2 extracellular domain Ⅳ in breast cancer / 中国药房

Human epidermal growth factor receptor 2 （HER2）-positive breast cancer is aggressive and prone to metastasis，and the applications of HER2 agents have improved the prognosis of patients with HER2-positive breast cancer. Among the marketed HER2 agents，macromolecular monoclonal antibodies that target the extracellular domain Ⅳ of HER2 were the cornerstone drugs of HER2-positive breast cancer，including trastuzumab，inetetamab，and margetuximab. Trastuzumab is available for the full-line treatment of breast cancer with sufficient proof of evidence-based medicine，sufficient practical experience and controllable safety. Inetetamab and trastuzumab have similar efficacy and controllable safety in HER2-positive metastatic breast cancer and neoadjuvant/ adjuvant therapy. Margetuximab focuses on patients carrying the CD16A-158F allele，and is an option of posterior line treatment for advanced breast cancer. It is necessary to select the most suitable drugs clinically according to the specific condition of the patient.

Network pharmacology and molecular docking reveal the mechanism of resveratrol in oral squamous cell carcinoma treatment / 口腔疾病防治

Objective@#To explore the molecular mechanism of resveratrol (RES) in the treatment of oral squamous cell carcinoma (OSCC) through the use of biological information methods such as network pharmacology and molecular docking and to provide a theoretical reference for the clinical application of RES in the treatment of OSCC.@*Methods@#The Swiss Target Prediction(http://www.swisstargetprediction.ch), SEA (http://sea.bkslab.org)database, and Pharm mapper database(http://lilab-ecust.cn) were used to retrieve RES-related targets, and the DISGENET (www.disgenet.org), OMIM (https://omim.org) and GeneCards (https://www.genecards.org) databases were used to screen OSCC disease targets. The intersection of drugs and disease targets was determined, and Cytoscape 3.7.2 software was used to construct a "drug-diseasetarget pathway" network. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to construct a target protein interaction network, and the DAVID database was used for enrichment analysis of key proteins. Finally, molecular docking validation of key proteins was performed using AutoDock and PyMOL. The enrichment analysis and molecular docking results were integrated to predict the possible molecular mechanisms of RES treatment in OSCC; western blot was used to determine the effect of resveratrol at different concentrations (50, 100) μmol/L on the expression of Src tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), estrogen receptor gene 1 (ESR1), and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway proteins in OSCC HSC-3 cells.@*Results@#A total of 243 targets of RES drugs and 6 094 targets of OSCC were identified. A total of 116 potential common targets were obtained by intersecting drugs with disease targets. These potential targets mainly participate in biological processes such as in vivo protein self-phosphorylation, peptide tyrosine phosphorylation, transmembrane receptor protein tyrosine kinase signaling pathway, and positive regulation of RNA polymerase Ⅱ promoter transcription, and they interfere with the PI3K/AKT signaling pathway to exert anti-OSCC effects. The docking results of resveratrol with OSCC molecules indicated that key targets, such as EGFR, ESR1, and SRC, have good binding activity. The results of cell-based experiments showed that resveratrol inhibited the protein expression of SRC, EGFR, ESR1, p-PI3K, and p-AKT in HSC-3 cells in a dose-dependent manner.@*Conclusion@#RES can inhibit the expression of its targets EGFR, ESR1, SRC, p-PI3K, and p-AKT in OSCC cells.

Hydroxysafflor Yellow A Promotes HaCaT Cell Proliferation and Migration by Regulating HBEGF/EGFR and PI3K/AKT Pathways and Circ_0084443 / 中国结合医学杂志

OBJECTIVE@#To investigate the effect and possible mechanism of hydroxysafflor yellow A (HSYA) on human immortalized keratinocyte cell proliferation and migration.@*METHODS@#HaCaT cells were treated with HSYA. Cell proliferation was detected by the cell counting kit-8 assay, and cell migration was measured using wound healing assay and Transwell migration assay. The mRNA and protein expression levels of heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF), EGF receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF-1α) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. Circ_0084443-overexpressing HaCaT cells and empty plasmid HaCaT cells were constructed using the lentiviral stable transfection and treated with HSYA. The expression of circ_0084443 was detected by qRT-PCR.@*RESULTS@#HSYA (800 µmol/L) significantly promoted HaCaT cell proliferation and migration (P<0.05 or P<0.01). It also increased the mRNA and protein expression levels of HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α, and increased the phosphorylation levels of PI3K and AKT (P<0.05 or P<0.01). Furthermore, HSYA promoted HaCaT cell proliferation and migration via the HBEGF/EGFR and PI3K/AKT/mTOR signaling pathways (P<0.01). Circ_0084443 attenuated the mRNA expression levels of HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α (P<0.05). HSYA inhibited the circ_0084443 expression, further antagonized the inhibition of circ_0084443 on HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α, and promoted the proliferation of circ_0084443-overexpressing HaCaT cells (P<0.05 or P<0.01). However, HSYA could not influence the inhibitory effect of circ_0084443 on HaCaT cell migration (P>0.05).@*CONCLUSION@#HSYA played an accelerative role in HaCaT cell proliferation and migration, which may be attributable to activating HBEGF/EGFR and PI3K/AKT signaling pathways, and had a particular inhibitory effect on the keratinocyte negative regulator circ_0084443.

Progress of Immunotherapy in EGFR-mutated Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC.
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Effects of rosmarinic acid and doxorubicine on an ovarian adenocarsinoma cell line (OVCAR3) via the EGFR pathway

Purpose: We aimed to reveal the effects of rosmarinic acid (RA), which has come to the forefront with its antitumor and antioxidant properties in many studies recently in the ovarian adenocarcinoma cell line, on the epidermal growth factor receptor (EFGR) signaling pathway in the presence of doxorubicin (DOX). Methods: Ovarian adenocarcinoma cell line (OVCAR3) and human skin keratinocyte cell line human skin keratinocyte cell line (HaCaT) were used as control. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was applied to determine the effect of RA and DOX on the proliferation of OVCAR3 and HaCaT cells. Bcl2 expression and epidermal growth factor receptor (EGFR) and western blot analysis were performed to determine the expression levels of the markers. Results: It was determined that RA (IC50 = 437.6 µM) and DOX (IC50 = 0.08 µM) have the ability to inhibit the proliferation of OVCAR3 cells and induce apoptosis in a 72-hour time and dose-dependent manner. Western blot showed that the expression level of Bcl-2 and EGFR in OVCAR3 cells was down-regulated by RA and DOX. Conclusions: Apoptosis in OVCAR3 cells can potentially be induced by RA via the EGFR pathway, and RA may be a potent agent for cancer therapy.

Ozonoterapia como apoyo en el tratamiento de la úlcera del pie diabético. Presentación de un caso

Una de las complicaciones más comunes de la diabetes mellitus es la úlcera del pie diabético, como una fuente importante de morbilidad y mortalidad. Se presenta el caso de una paciente de 43 años, con diagnóstico de diabetes mellitus tipo 2, de siete años de evolución, remitida desde el Cuerpo de Guardia del Policlínico Universitario Dr. Mario Muñoz Monroy, de Abreus, con el diagnóstico de pie diabético neuroinfeccioso complicado con un absceso. Se realizó drenaje del absceso, modificación del tratamiento con insulina y desbridamiento de la lesión. Además, se indicó antibiótico y Heberprot-P®. Ante la ausencia de evolución satisfactoria, se realizó nuevo desbridamiento, con amputación de tercer y cuarto dedos del pie izquierdo; se retomó el tratamiento inicial, eta vez combinado con ozonoterapia vía local y rectal. A partir de la semana 18 la paciente evolucionó favorablemente, con presencia de buena granulación, desaparición gradual del dolor y aceleración del proceso de cicatrización completa de la lesión, además de conseguir un control metabólico eficiente. El caso descrito confirma la eficacia y seguridad del uso combinado del Heberprot-P® y la terapia con ozono.

One of the most common complications of diabetes mellitus is diabetic foot ulcer, as an important source of morbidity and mortality. The case of a 43-years-old patient with a diagnosis of type 2 diabetes mellitus, of seven years of evolution, referred from the Emergency Department of the Dr. Mario Muñoz Monroy University Polyclinic, Abreus, with the diagnosis of neuroinfectious diabetic foot complicated with an abscess is presented. Drainage of the abscess, modification of insulin treatment, and debridement of the lesion were performed. In addition, antibiotics and Heberprot-P® were indicated. In the absence of satisfactory evolution, new debridement was performed, with amputation of the third and fourth toes of the left foot; the initial treatment was resumed, this time combined with local and rectal ozone therapy. From week 18 on, the patient progressed favorably, with the presence of good granulation, gradual disappearance of pain and acceleration of the complete healing process of the lesion, in addition to achieving efficient metabolic control. The described case confirms the efficacy and safety of the Heberprot-P® combined use and ozone therapy.

Heberprot-P® en el tratamiento de trauma vascular distal / Heberprot-P® in the treatment of distal vascular trauma

Introducción: Los traumatismos constituyen causa frecuente de consulta. Entre sus localizaciones más comunes se encuentran las extremidades inferiores. El Heberprot-P® resulta un factor de crecimiento epidérmico que se ha utilizado durante más de una década para la cicatrización de las úlceras del pie diabético con excelentes resultados. Ampliar su utilización a otras patologías, incluso de etiología traumática, permitiría expandir las posibilidades terapéuticas para la cicatrización de las heridas. Objetivo: Exponer el resultado de la aplicación del Heberprot-P® en una amputación transtarsiana en un paciente portador de un trauma vascular distal. Presentación del caso: Paciente masculino de 23 años con antecedentes de salud. Luego de traumatismo por accidente de tránsito presentó fractura de huesos del metatarso y la sección total de la arteria pedia del pie izquierdo, lo cual provocó una gangrena húmeda de la extremidad. Por este motivo se realizó una amputación transtarsiana del pie. Se usó el Heberprot-P® como terapia para acortar el tiempo de cicatrización. Conclusiones: El Heberprot-P® resultó útil para la evolución de la herida como consecuencia de un trauma vascular, al evitar una amputación mayor, acelerar el proceso de cicatrización y conservar una extremidad funcional, lo que demostró que puede constituir una terapia eficaz para las heridas de difícil cicatrización, independientemente de su etiología(AU)

Introduction: Trauma is a frequent cause of consultation. Among its most common locations are the lower extremities. Heberprot-P® is an epidermal growth factor that has been used for more than a decade for the healing of diabetic foot ulcers with excellent results. Extending its use to other pathologies, including traumatic etiology ones, would expand the therapeutic possibilities for wound healing. Objective: To present the result of the application of Heberprot-P® in a Chopart´s amputation in a patient with distal vascular trauma. Case presentation: A 23-year-old male patient with a health history. After trauma from a traffic accident, he presented a fracture of the bones of the metatarsus and the whole section of the left foot´s pedis artery, which caused a wet gangrene of the extremity. For this reason, a Chopart´s amputation of the foot was performed. Heberprot-P® was used as therapy to shorten healing time. Conclusions: Heberprot-P® was useful for wound evolution as a result of vascular trauma, avoiding major amputation, accelerating the healing process and preserving a functional limb, which showed that it can be an effective therapy for wounds that are difficult to heal, regardless of their etiology(AU)

Investigation the Effect of Human Recombinant Epidermal Growth Factor on Rotator Cuff Healing: An Experimental Model / Investigação do efeito do fator de crescimento epidérmico recombinante humano na cicatrização do manguito rotador: Um modelo experimental

Abstract Objective To investigate the effectiveness of human recombinant epidermal growth factor in the healing of rotator cuff tear in the rabbit shoulder. Methods Rotator cuff tears (RCTs) were experimentally created on both shoulders of 20 New Zealand rabbits. The rabbits were divided into the following groups: RCT (sham group; n = 5), RCT + EGF (EGF group; n = 5), RCT + transosseous repair (repair group; n = 5), and RCT + EGF + transosseous repair (combined repair + EGF group; n = 5). All rabbits were then observed for 3 weeks, and biopsies were taken from the right shoulders in the third week. After three more weeks of observation, all rabbits were sacrificed, and a biopsy removed from their left shoulders. All biopsy material was stained with haematoxylin & eosin (H&E) and vascularity, cellularity, the proportion of fibers and the number of fibrocartilage cells were evaluated under light microscope. Results The highest collagen amount and the most regular collagen sequence was detected in the combined repair + EGF group. The repair group and the EGF group showed higher fibroblastic activity and capillary formation when compared with the sham group, but the highest fibroblastic activity and capillary formation with highest vascularity was detected in the combined repair + EGF group (p < 0.001). EGF seems to improve wound healing in the repair of RCT. The EGF application alone, even without repair surgery, seems to be beneficial to RCT healing. Conclusion In addition to rotator cuff tear repair, application of human recombinant epidermal growth factor has an effect on rotator cuff healing in rabbit shoulders.

Resumo Objetivo Investigar a eficácia do fator de crescimento epidérmico (EGF) recombinante humano na cicatrização da lesão do manguito rotador no ombro de coelhos. Métodos As rupturas do manguito rotador (RMRs) foram criadas experimentalmente em ambos os ombros de 20 coelhos Nova Zelândia. Os coelhos foram divididos nos seguintes grupos: RMR (grupo controle; n = 5), RMR + EGF (grupo EGF; n = 5), RMR + reparo transósseo (grupo reparo; n = 5) e RMR + EGF + reparo transósseo (grupo reparo combinado+ EGF; n = 5). Todos os coelhos foram observados por 3 semanas, e amostras de biópsias foram coletadas do ombro direito na 3ª semana. Após mais 3 semanas de observação, todos os coelhos foram submetidos à eutanásia, e uma amostra de biópsia foi coletada dos ombros esquerdos. Todo o material de biópsia foi corado com hematoxilina e eosina (H&E) para avaliação de vascularidade, celularidade, proporção de fibras e número de células fibrocartilaginosas à microscopia óptica. Resultados O grupo reparo combinado + EGF apresentou a maior quantidade e a sequência mais regular de colágeno. O grupo reparo e o grupo EGF apresentaram maior atividade fibroblástica e formação capilar em comparação ao grupo controle, mas a maior atividade fibroblástica e a formação capilar com maior vascularidade foram detectadas no grupo reparo combinado + EGF (p < 0,001). O EGF parece melhorar a cicatrização da ferida no reparo da RMR. A aplicação isolada de EGF, mesmo sem cirurgia reparadora, parece melhorar a cicatrização da RMR. Conclusão Além do reparo da RMR, a aplicação de EGF recombinante humano auxilia a cicatrização do manguito rotador dos ombros de coelhos.

Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2/neu in gallbladder carcinoma in North Indian population

Background: Gallbladder carcinoma (GBC) although rare is most frequent malignant neoplasm of biliary tract system and sixth most common malignancy of digestive tract. GBC is more common in females and there are studies which show expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 neu (HER2/neu) in GBC suggesting possible molecules for targeted therapy, but results are inconsistent. Aims and Objectives: The aim of this study was to find out expression of ER, PR, and HER2/neu in GBC in North Indian population and their possible association with clinicopathological features. Materials and Methods: A total 59 resected cases of GBC diagnosed by histopathological examination were included in the study. Expression of ER, PR, and HER2/neu was accessed by immunohistochemistry method and correlated with various clinicopathological features. Results: ER expression was absent in all GBC cases. PR expression was present in only one case. Positive expression of HER2/neu was present in 13 (22%) cases, in which 12 cases were of conventional adenocarcinoma and one case was of papillary adenocarcinoma. Well and moderately differentiated tumor had significantly higher HER2/neu expression as compared to poorly differentiated tumors (P = 0.001). Pre-obese patients had significantly higher HER2/neu expression as compared to non-obese patients (P = 0.008). Conclusion: In our study, there was no expression of estrogen and PR in GBC in North Indian population. Although small in number, there is a subset of patients who overexpress HER2/neu receptor that may benefit from targeted therapy.

The therapeutic effect of Balanophora polysaccharide on acetic acid gastric ulcer in rats and its mechanism / 中国药理学通报

Aim To study the therapeutic effect of Balanophora polysaccharide(BPS)on gastric ulcer(GU)induced by acetic acid in rats and to investigateits mechanisms. Methods Sixty male SD rats were randomly divided into sham-operated group, GU model group, omeprazole positive group(3.6 mg·kg-1), and low, medium and high dose of BPS treatment groups(100, 200 and 400 mg·kg-1). The GU model group was prepared by acetic acid cautery method, and the morphology and pathological changes of ulcers were observed by visual observation combined with HE staining, and the ulcer area and inhibition rate were measured and calculated; superoxide dismutase(SOD)activity, malondialdehyde(MDA)content and glutathione peroxidase(GSH-PX)activity were measured by enzymatic assay; tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)content were detected by ELISA. The expression levels of epidermal growth factor(EGF)and epidermal growth factor receptor(EGFR)were measured by immunohistochemistry staining and Western blot. Results Compared with the sham-operated group, obvious ulcer damage was seen in the model group. Compared with the model group, the BPS-treated group showed a significant reduction in ulcer area, an increase in SOD and GSH-PX activity and EGF and EGFR expression levels, and a significant decrease in MDA, TNF-α and IL-6 content. Conclusions BPS has a therapeutic effect on GU in rats, and its mechanism may be related to the inhibition of oxidative stress, suppression of inflammatory stimuli and promotion of regenerative repair of gastric mucosa.

Construction and functional analysis of EGFRvIII CAR-T cells co-expressing IL-15 and CCL19 / 生物工程学报

The aim of this study was to investigate the functional characteristics and in vitro specific killing effect of EGFRvIII CAR-T cells co-expressing interleukin-15 and chemokine CCL19, in order to optimize the multiple functions of CAR-T cells and improve the therapeutic effect of CAR-T cells targeting EGFRvIII on glioblastoma (GBM). The recombinant lentivirus plasmid was obtained by genetic engineering, transfected into 293T cells to obtain lentivirus and infected T cells to obtain the fourth generation CAR-T cells targeting EGFRvIII (EGFRvIII-IL-15-CCL19 CAR-T). The expression rate of CAR molecules, proliferation, chemotactic ability, in vitro specific killing ability and anti-apoptotic ability of the fourth and second generation CAR-T cells (EGFRvIII CAR-T) were detected by flow cytometry, cell counter, chemotaxis chamber and apoptosis kit. The results showed that compared with EGFRvIII CAR-T cells, EGFRvIII-IL-15-CCL19 CAR-T cells successfully secreted IL-15 and CCL19, and had stronger proliferation, chemotactic ability and anti-apoptosis ability in vitro (all P < 0.05), while there was no significant difference in killing ability in vitro. Therefore, CAR-T cells targeting EGFRvIII and secreting IL-15 and CCL19 are expected to improve the therapeutic effect of glioblastoma and provide an experimental basis for clinical trials.

Consensus on the clinical use of CDK4/6 inhibitors for the treatment of hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer (2023 edition) / 中华肿瘤杂志

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have led transformative breakthrough of clinical therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER-2)-negative breast cancer patients. CDK4/6 inhibitors that have been marketed in China include Ribociclib, Palbociclib, Abemaciclib and Dalpiciclib. For HR-positive HER-2-negative locally advanced and metastatic breast cancer, CDK4/6 inhibitors combined with endocrine therapy have become standard regimen, which can prolong the survival of patients. In the adjuvant treatment stage of early breast cancer, CDK4/6 inhibitors have also achieved positive results and been approved for indications. At present, CDK4/6 inhibitors have been widely used in clinical practice in China. In order to further improve the standardized application of CDK4/6 inhibitors in China, the Breast Cancer Expert Committee of the National Center for Cancer Quality Control and the Professional Committee of Clinical Research of Cancer Drugs of the Chinese Anti-Cancer Association organized the related expert to update the consensus based on the "CDK4/6 inhibitor consensus on clinical application of in the treatment of hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer (2021 edition)" . The updated consensus systematically introduces the pharmacological characteristics, drug monitoring and adverse event management, etc., of CDK4/6 inhibitors to promote the accuracy of clinical decision-making with the ultimate goal to prolong the overall survival of patients and improve the quality of life.

Clinicopathological Characteristics and Therapeutic Effect of Patients with Non-small Cell Lung Cancer and Uncommon EGFR Mutations / 肿瘤防治研究

Objective To investigate the clinicopathological characteristics and treatment effect of patients with non-small cell lung cancer (NSCLC) and uncommon epidermal growth factor receptor (EGFR) gene mutations. Methods Real-time fluorescence quantitative PCR was used to detect the mutation of EGFR in 674 samples of patients with NSCLC.The correlation between uncommon EGFR mutations and clinicopathological characteristics was analyzed. Results The EGFR mutation rate was 47.92%, of which the incidence of uncommon EGFR mutations was 5.19%, showed the presence of ex18 G719 A/S/C (G719X)(1.63%), ex20ins (1.04%), ex21 L861Q (0.74%), and compound mutations (1.78%).Correlation analysis showed that uncommon EGFR mutations were more common in women, non-smokers, patients with high-medium differentiation and adenocarcinoma, and patients were more prone to brain and bone metastasis (all P < 0.05).NSCLC with uncommon EGFR mutations showed no significant differences in clinical and pathological features compared with those with common sensitive mutations (all P > 0.05).Follow-up information was available on 31 patients, with a median follow-up time of 10 months, of which 23 were in advanced stage.Among eight patients with G719X mutation in late stage, seven patients used EGFR tyrosine kinase inhibitor (EGFR TKIs)(five of them used afatinib) in the first line and had a median PFS of 12 months; one patient received chemotherapy with pemetrexed and carboplatin and had PFS of seven months, which was lower than that of the TKI group.Among four patients with L861Q mutation in late stage, one patient was untreated and the three remaining were treated with TKI in the first line and had a median PFS of eight months.The patient who was treated with afatinib and bevacizumab was still stable after 11 months of follow-up.Two patients with EGFR ex20ins in advanced stage were treated with chemotherapy and bevacizumab.Nine patients with compound mutations in advanced stage were treated with TKI; among which, five patients harboring T790M compound mutations were treated with third-generation TKI and had a median PFS of more than 10 months. Conclusion The correlation between specific uncommon EGFR mutation and clinical pathological characteristics varies.For advanced patients with uncommon EGFR mutations (except for ex20ins), TKI is generally chosen as the first-line clinical treatment.Afatinib is recommended for advanced NSCLC patients with G719X and L861Q mutations.Third-generation TKI has significant efficacy in patients with complex mutations containing T790M.

Visual analysis of tyrosine kinase inhibitors in HER2 positive breast cancer / 中国药房

OBJECTIVE To analyze the research status， hotspot and development trend of tyrosine kinase inhibitors （TKIs） in the treatment of human epidermal growth factor receptor 2 （HER2） positive breast cancer. METHODS The literature related to TKIs in the treatment of HER2 positive breast cancer were searched from the Web of Science core collection database； the author， country/region， institution， subject field， journal and keywords was visualized by CiteSpace 6.1.R3 software. RESULTS A total of 732 pieces of literature were included， and the number of literature published showed an increasing trend year by year. The number of literature published in the United States was the largest （center degree 0.10）， and the number of literature published in China ranked second （center degree 0.05）. The most published and cited authors were Crown from St. Vincent’s University Hospital in Australia and Slamon from University of California， Los Angeles in the United States； the institution with the highest number of literature was the University of Texas MD Anderson Cancer Center， and the journal with the highest number of literature was the Journal of Clinical Oncology. The research mainly focused on five aspects： HER2 positive breast cancer treatment drugs， TKIs receptor， TKIs mechanism of action， HER2 positive breast cancer brain metastasis， and TKIs clinical trials. The main frontier areas and development trends were the combination of TKIs with other drugs or therapies to enhance targeting and reduce toxic side effects. CONCLUSIONS The study of TKIs in the treatment of HER2 positive breast cancer has attracted the attention of scholars at home and abroad. Chinese scholars and research teams need to strengthen cooperation and communication in the future， and cooperation with other countries should be strengthened in terms of the efficacy and safety of TKIs alone and combined with other drugs in the treatment of HER2 positive breast cancer.

Relationship Between p53， EGFR and Radiotherapy Resistance of Head and Neck Squamous Cell Carcinoma / 中山大学学报(医学科学版)

Head and neck cancers are the seventh most common type of cancer in the world， among which more than 90% are squamous cell carcinomas（HNSCC）. Radiotherapy is one of the important treatments for HNSCC， and the sensitivity of tumor cells to the therapy is a key factor influencing the efficacy of treatment. p53 is one of the most common mutated genes in HNSCC， and epidermal growth factor receptor（EGFR） is overexpressed in many HNSCC. Both of these genes could enhance cellular DNA repair， which may be related to the radiotherapy resistance of HNSCC. This review focuses on the mechanisms by which tumor cells escape radiation-mediated apoptosis through p53 and EGFR-mediated DNA repair.

Research progress of furmonertinib for EGFR-mutated non-small cell lung cancer / 中国药房

Lung cancer is mainly non-small cell lung cancer （NSCLC）. NSCLC is often associated with epidermal growth factor receptor （EGFR） gene mutations. Currently， epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKI） are the preferred first-line treatment option for EGFR-mutated NSCLC. Furmonertinib is the second third-generation EGFR-TKI marketed in China， which is developed independently by China. In this review， it is found that furmonertinib has dual activity， strong tumor suppression， high selectivity， and high safety profile， and is effective in the treatment of EGFR-sensitive mutation， EGFR exon 20 T790M resistance mutation， EGFR exon 20 insertion mutation， and central nervous system metastasis NSCLC， and its relevant clinical trials are only enrolled in Chinese patients， which is more guidance for Chinese NSCLC patients in China.

Efficacy and safety of olaparib in adjuvant therapy of BRCA1/2 mutated HER2-negative breast cancer：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of olaparib in adjuvant therapy of breast cancer susceptibility gene （BRCA） 1/2 mutated human epidermal growth factor receptor 2 （HER2）-negative breast cancer， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from CNKI， VIP， Wanfang data， PubMed， ScienceDirect， the Cochrane Library and Embase databases， randomized controlled trials about adjuvant therapy of olaparib （trial group） versus adjuvant therapy of other drugs （control group） were collected. After literature screening and data extraction， meta-analysis， publication bias analysis and sensitivity analysis were performed by using RevMan5.4 software. RESULTS A total of 5 randomized controlled trials were included， with a total of 2 633 patients， including 1 495 cases in trial group and 1 174 cases in control group. Meta-analysis showed that in terms of efficacy， compared with control group， overall survival [HR＝1.02， 95%CI （1.01，1.03）， P＝0.000 8] and progression-free survival [HR＝1.78， 95%CI（1.46，2.17）， P＜0.000 01] were longer significantly in the trial group. In terms of safety， compared with the control group， the incidence of adverse drug reactions at any level in the trial group was higher [RR＝1.41， 95%CI （1.12， 1.78）， P＝0.004]， while there was no statistically significant difference in the incidence of adverse drug reactions above level 3 between the two groups [RR＝1.75， 95%CI （0.82， 3.74）， P＝0.15]. The results of publication bias indicated that the possibility of publication bias in this study was relatively low. The results of sensitivity analysis showed that the results obtained in this study were robust. CONCLUSIONS Compared with patients without adjuvant therapy of olaparib， adjuvant therapy of olaparib can prolong overall survival and progression-free survival of patients with BRCA1/2 mutated HER2-negative breast cancer，but the risk of adverse drug reactions is relatively high.

A Rare Case of Lung Adenocarcinoma with EGFR L833V/H835L Co-mutation and Literature Review / 中国肺癌杂志

Epidermal growth factor receptor (EGFR) mutations are the most common driver genes in the development of non-small cell lung cancer (NSCLC), of which mutations in exons 18-21 are frequent, especially the loss of exon 19 and exon 21 L858R mutation are the most frequent. Other rare gene mutations are rare. Simultaneous occurrence of two or more rare EGFR mutations are extremely rare in lung cancer, and the incidence of EGFR L833V/H835L rare gene compound mutations is very low, and there is little clinical data and evidence of relevant treatment methods. Some EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are effective in treating lung cancer patients with rare gene mutations. In this article, we reported a case of NSCLC patient with a rare gene compound mutation EGFR L833V/H835L, who responded to Afatinib in combination with Anilotinib treatment well after 5 months of treatment, and computed tomography (CT) showed shrinkage of lung lesions. Meanwhile, we also compiled previously reported NSCLC patients with EGFR L833V/H835L rare gene compound mutation and summarized the characteristics of this group of patients and the effect of applying different kinds of EGFR-TKIs treatment.
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Effect of Wnt/β-catenin signaling pathway in neural differentiation of human bone marrow mesenchymal stem cells / 中国修复重建外科杂志

OBJECTIVE@#To explore the effect of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and the combination of bFGF and EGF in the neural differentiation of human bone marrow mesenchymal stem cells (hBMSCs), and the role of Wnt/β-catenin signaling pathway in this process.@*METHODS@#The identified 4th-generation hBMSCs were divided into five groups according to different induction conditions, namely control group (group A), EGF induction group (group B), bFGF induction group (group C), EGF and bFGF combined induction group (group D), and EGF, bFGF, and Dickkopf-related protein 1 (DKK-1) combined induction group (group E). After 7 days of continuous induction, the cell morphology was observed by inverted fluorescence phase contrast microscopy, levels of genes that were related to neural cells [Nestin, neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP-2), and glial fibrillary acidic protein (GFAP)] and key components of the Wnt/β-catenin signaling pathway (β-catenin and Cyclin D1) were detected by RT-PCR, and the levels of proteins that were related to neural cells (Nestin and GFAP) as well as genes that were involved in Wnt/β-catenin signaling pathway [β-catenin, phosphorylation β-catenin (P-β-catenin), Cytoplasmic β-catenin, and Nuclear β-catenin] were explored by cellular immunofluorescence staining and Western blot.@*RESULTS@#When compared to groups A and B, the typical neuro-like cell changes were observed in groups C-E, and most obviously in group D. RT-PCR showed that the relative expressions of Nestin, NSE, and MAP-2 genes in groups C-E, the relative expressions of GFAP gene in groups D and E, the relative expression of NSE gene in group B, the relative expressions of β-catenin gene in groups C and D, and the relative expressions of Cyclin D1 gene in groups B-D significantly increased when compared with group A ( P<0.05). Compared with group E, the relative expressions of Nestin, NSE, MAP-2, GFAP, β-catenin, and CyclinD1 genes significantly increased in group D ( P<0.05); compared with group C, the relative expression of Nestin gene in group D significantly decreased ( P<0.05), while NSE, MAP-2, and GFAP genes significantly increased ( P<0.05). The cellular immunofluorescence staining showed that the ratio of NSE- and GFAP-positive cells significantly increased in groups C-E than in group A, in group D than in groups C and E ( P<0.05). Western blot assay showed that the relative expression of NSE protein was significantly higher in groups C and D than in group A and in group D than in groups C and E ( P<0.05). In addition, the relative expression of GFAP protein was significantly higher in groups C-E than in group A and in group D than in group E ( P<0.05). Besides, the relative expressions of β-catenin, Cytoplasmic β-catenin, Nuclear β-catenin, and the ratio of Nuclear β-catenin to Cytoplasmic β-catenin were significantly higher in groups C and D than in group A and in group D than in group E ( P<0.05), whereas the relative expression of P-β-catenin protein was significantly lower in groups C and D than in group A and in group D than in group E ( P<0.05).@*CONCLUSION@#Different from EGF, bFGF can induce neural differentiation of hBMSCs. In addition, EGF can enhance the hBMSCs neural differentiation of bFGF, while the Wnt/β-catenin signaling pathway may play a positive regulatory role in these processes.

Clinical characteristics and prognosis analysis of patients with HER2 positive gastric cancer / 国际外科学杂志

Objective:To investigate the correlation of human epidermal growth receptor 2 (HER2) with clinicopathological characteristics and its postoperative prognostic value in patients with gastric cancer.Methods:The clinicopathological data of 543 patients with gastric cancer who underwent open radical gastrectomy were retrospectively analyzed in the Gastrointestinal Surgery Department of Jiangyin People′s Hospital Affiliated to Southeast University from June 2011 to December 2016, including 404 males and 139 females, aged from 26 to 84 years old. According to the results of HER2 immunohistochemical staining, gastric cancer patients were divided into HER2 0+ group ( n=427), HER2 1+ group ( n=56), HER2 2+ group ( n=29) and HER2 3+ group ( n=31), and the differences in clinicopathological indicators of the four groups were compared. Furthermore, HER2 0+ and 1+ gastric cancer patients were classified as HER2-negative group( n=26), and HER2 3+ as HER2-positive group( n=26). Propensity score matching method was used to balance the basic data variables related to prognosis of the two groups, and Kaplan-Meier method was used for survival analysis. Cox risk regression model was used to analyze the risk factors associated with postoperative survival in patients with HER2-positive gastric cancer. Results:The overexpression rate of HER2 in gastric cancer patients was 5.7% (31/543). The expression level of HER2 was significantly correlated with gender ( χ2=8.30, P=0.040), tumor longitudinal location ( χ2=22.86, P=0.029) and histological differentiation ( χ2=13.27, P=0.004). There was no significant correlation between median survival time and HER2 expression level( χ2=5.44, P=0.142). After propensity score matching, the median survival time of gastric cancer in the HER2-positive group was 23 months. Univariate and multivariate analysis showed that ABO blood group ( HR: 1.619, 95% CI: 1.081-2.423, P=0.019) was an independent risk factor for prognosis of HER2-positive gastric cancer. Conclusion:The expression of HER2 is higher in men, cardia fundus and high and medium differentiated gastric adenocarcinoma, but there is no significant correlation between the expression level of HER2 and the median survival time of gastric cancer. ABO blood group may be an independent risk factor for the survival of HER2-positive gastric cancer.