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.

Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation / 中国结合医学杂志

OBJECTIVE@#To investigate the mechanism of the effect of Astragalus membranaceus (A. membranaceus) on lung adenocarcinoma at the molecular level to elucidate the specific targets according to the network pharmacology approach.@*METHODS@#The active components of A. membranaceus and their potential targets were collected from the Traditional Chinese Medicine Systems Pharmacology Database. Lung adenocarcinoma-associated genes were acquired based on GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGKB, and Therapeutic Targets databases. The PI3K/AKT signaling pathway-related genes were obtained using Reactome portal. Networks of "ingredient-target" and "ingredient-target-pathway-disease" were constructed using the Cytoscape3.6.0 software. The relationships among targets were analyzed according protein-protein interaction (PPI) network. Finally, molecular docking was applied to construct the binding conformation between active ingredients and core targets. Cell counting kit 8 (CCK8) and Western blot assays were performed to determine the mechanism of the key ingredient of A. membranaceus.@*RESULTS@#A total of 20 active components and their 329 targets, and 7,501 lung adenocarcinoma-related genes and 130 PI3K/AKT signaling pathway-related genes were obtained. According to Venn diagram and PPI network analysis, 2 mainly active ingredients, including kaempferol and quercetin, and 6 core targets, including TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR, were identified. The two important active ingredients of A. membranaceus, kaempferol and quercetin, exert the therapeutic effect in lung adenocarcinoma partly by acting on the 6 core targets (TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR) of PI3K/AKT signaling pathway. Expressions of potential targets in lung adenocarcinoma and normal samples were analyzed by using UALCAN portal and found that ERBB2 was overexpressed in lung adenocarcinoma tissues and upregulation of it correlated with clinicopathological characteristics. Finally, quercetin repressed viabilities of lung adenocarcinoma cells by targeting ERBB2 on PI3K/AKT signaling confirmed by CCK8 and Western blot.@*CONCLUSION@#Our finding unraveled that an active ingredient of A. membranaceus, quercetin, significantly inhibited the lung adenocarcinoma cells proliferation by repressing ERBB2 level and inactivating the PI3K/AKT signaling pathway.

Effect of ascorbic acid and epidermal growth factor in a rat tibia defect

Purpose: Bone repair aims to restore the anatomical, biomechanical, and functional integrity of the affected structure. Here we study the effects of ascorbic acid (AA) and epidermal growth factor (EGF) applied in a single dose and in combination on the repair of a noncritical bone defect model. Methods: Twenty-four rats were divided into four groups: an intact G-1 control group, and three groups that underwent a noncritical bone defect in the right tibia: G-2 treated with AA, G-3 treated with EGF, and G-4 treated with AA in combination with EGF. After 21 days of treatment, rats were sacrificed, the tibias were dissected and a destructive biomechanical analysis of three-point flexion test was performed in a universal testing machine; the values of stiffness, resistance, maximum energy, and energy at maximum load were statistically compared. Results: G-3 and G-4 recovered the biomechanical properties of strength and stiffness of an intact tibia 3 weeks after their application. Not so the energy and energy at maximum load. For G-2, only the stiffness of an intact tibia was recovered. Conclusion: EGF and AA-EGF applied to a noncritical bone defect in the rat tibia favors the recovery of bone resistance and stiffness.

Influence of autologous adipose stem cell matrix gel on wound healing and scar hyperplasia of full-thickness skin defects in rabbit ears / 中华烧伤杂志

Objective: To investigate the influence of autologous adipose stem cell matrix gel on wound healing and scar hyperplasia of full-thickness skin defects in rabbit ears, and to analyze the related mechanism. Methods: Experimental research methods were adopted. The complete fat pads on the back of 42 male New Zealand white rabbits aged 2 to 3 months were cut to prepare adipose stem cell matrix gel, and a full-thickness skin defect wound was established on the ventral side of each ear of each rabbit. The left ear wounds were included in adipose stem cell matrix gel group (hereinafter referred to as matrix gel group), and the right ear wounds were included in phosphate buffer solution (PBS) group, which were injected with autologous adipose stem cell matrix gel and PBS, respectively. The wound healing rate was calculated on post injury day (PID) 7, 14, and 21, and the Vancouver scar scale (VSS) scoring of scar tissue formed on the wound (hereinafter referred to as scar tissue) was performed in post wound healing month (PWHM) 1, 2, 3, and 4. Hematoxylin-eosin staining was performed to observe and measure the histopathological changes of wound on PID 7, 14, and 21 and the dermal thickness of scar tissue in PWHM 1, 2, 3, and 4. Masson staining was performed to observe the collagen distribution in wound tissue on PID 7, 14, and 21 and scar tissue in PWHM 1, 2, 3, and 4, and the collagen volume fraction (CVF) was calculated. The microvessel count (MVC) in wound tissue on PID 7, 14, and 21 and the expressions of transforming growth factor β1 (TGF-β1) and α smooth muscle actin (α-SMA) in scar tissue in PWHM 1, 2, 3, and 4 were detected by immunohistochemical method, and the correlation between the expression of α-SMA and that of TGF-β1 in scar tissue in matrix gel group was analyzed. The expressions of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) in wound tissue were detected by enzyme-linked immunosorbent assay on PID 7, 14, and 21. The number of samples at each time point in each group was 6. Data were statistically analyzed with analysis of variance for repeated measurement, analysis of variance for factorial design, paired sample t test, least significant difference test, and Pearson correlation analysis. Results: On PID 7, the wound healing rate in matrix gel group was (10.3±1.7)%, which was close to (8.5±2.1)% in PBS group (P>0.05). On PID 14 and 21, the wound healing rates in matrix gel group were (75.5±7.0)% and (98.7±0.8)%, respectively, which were significantly higher than (52.7±6.7)% and (90.5±1.7)% in PBS group (with t values of 5.79 and 10.37, respectively, P<0.05). In PWHM 1, 2, 3, and 4, the VSS score of scar tissue in matrix gel group was significantly lower than that in PBS group (with t values of -5.00, -2.86, -3.31, and -4.45, respectively, P<0.05). Compared with the previous time point within the group, the VSS score of scar tissue at each time point after wound healing in the two groups was significantly increased (P<0.05), except for PWHM 4 in matrix gel group (P>0.05). On PID 7, the granulation tissue regeneration and epithelialization degree of the wounds between the two groups were similar. On PID 14 and 21, the numbers of fibroblasts, capillaries, and epithelial cell layers in wound tissue of matrix gel group were significantly more than those in PBS group. In PWHM 1, 2, 3, and 4, the dermal thickness of scar tissue in matrix gel group was significantly thinner than that in PBS group (with t values of -4.08, -5.52, -6.18, and -6.30, respectively, P<0.05). Compared with the previous time point within the group, the dermal thickness of scar tissue in the two groups thickened significantly at each time point after wound healing (P<0.05). Compared with those in PBS group, the collagen distribution in wound tissue in matrix gel group was more regular and the CVF was significantly increased on PID 14 and 21 (with t values of 3.98 and 3.19, respectively, P<0.05), and the collagen distribution in scar tissue was also more regular in PWHM 1, 2, 3, and 4, but the CVF was significantly decreased (with t values of -7.38, -4.20, -4.10, and -4.65, respectively, P<0.05). Compared with the previous time point within the group, the CVFs in wound tissue at each time point after injury and scar tissue at each time point after wound healing in the two groups were significantly increased (P<0.05), except for PWHM 1 in matrix gel group (P>0.05). On PID 14 and 21, the MVC in wound tissue in matrix gel group was significantly higher than that in PBS group (with t values of 4.33 and 10.10, respectively, P<0.05). Compared with the previous time point within the group, the MVC of wound at each time point after injury in the two groups was increased significantly (P<0.05), except for PID 21 in PBS group (P>0.05). In PWHM 1, 2, 3, and 4, the expressions of TGF-β1 and α-SMA in scar tissue in matrix gel group were significantly lower than those in PBS group (with t values of -2.83, -5.46, -5.61, -8.63, -10.11, -5.79, -8.08, and -11.96, respectively, P<0.05). Compared with the previous time point within the group, the expressions of TGF-β1 and α-SMA in scar tissue in the two groups were increased significantly at each time point after wound healing (P<0.05), except for the α-SMA expression in matrix gel group in PWHM 4 (P>0.05). There was a significantly positive correlation between the expression of α-SMA and that of TGF-β1 in scar tissue in matrix gel group (r=0.92, P<0.05). On PID 14 and 21, the expressions of VEGF (with t values of 6.14 and 6.75, respectively, P<0.05) and EGF (with t values of 8.17 and 5.85, respectively, P<0.05) in wound tissue in matrix gel group were significantly higher than those in PBS group. Compared with the previous time point within the group, the expression of VEGF of wound at each time point after injury in the two groups was increased significantly (P<0.05), and the expression of EGF was decreased significantly (P<0.05). Conclusions: Adipose stem cell matrix gel may significantly promote the wound healing of full-thickness skin defects in rabbit ears by promoting collagen deposition and expressions of VEGF and EGF in wound tissue, and may further inhibit the scar hyperplasia after wound healing by inhibiting collagen deposition and expressions of TGF-β1 and α-SMA in scar tissue.

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)

Investigation on the growth factor regulatory network of dermal fibroblasts in mouse full-thickness skin defect wounds based on single-cell RNA sequencing / 中华烧伤杂志

Objective: To explore the heterogeneity and growth factor regulatory network of dermal fibroblasts (dFbs) in mouse full-thickness skin defect wounds based on single-cell RNA sequencing. Methods: The experimental research methods were adopted. The normal skin tissue from 5 healthy 8-week-old male C57BL/6 mice (the same mouse age, sex, and strain below) was harvested, and the wound tissue of another 5 mice with full-thickness skin defect on the back was harvested on post injury day (PID) 7. The cell suspension was obtained by digesting the tissue with collagenase D and DNase Ⅰ, sequencing library was constructed using 10x Genomics platform, and single-cell RNA sequencing was performed by Illumina Novaseq6000 sequencer. The gene expression matrices of cells in the two kinds of tissue were obtained by analysis of Seurat 3.0 program of software R4.1.1, and two-dimensional tSNE plots classified by cell group, cell source, and gene labeling of major cells in skin were used for visual display. According to the existing literature and the CellMarker database searching, the expression of marker genes in the gene expression matrices of cells in the two kinds of tissue was analyzed, and each cell group was numbered and defined. The gene expression matrices and cell clustering information were introduced into CellChat 1.1.3 program of software R4.1.1 to analyze the intercellular communication in the two kinds of tissue and the intercellular communication involving vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) signal pathways in the wound tissue, the relative contribution of each pair of FGF subtypes and FGF receptor (FGFR) subtypes (hereinafter referred to as FGF ligand receptor pairs) to FGF signal network in the two kinds of tissue, and the intercellular communication in the signal pathway of FGF ligand receptor pairs with the top 2 relative contributions in the two kinds of tissue. The normal skin tissue from one healthy mouse was harvested, and the wound tissue of one mouse with full-thickness skin defect on the back was harvested on PID 7. The multiple immunofluorescence staining was performed to detect the expression and distribution of FGF7 protein and its co-localized expression with dipeptidyl peptidase 4 (DPP4), stem cell antigen 1 (SCA1), smooth muscle actin (SMA), and PDGF receptor α (PDGFRα) protein. Results: Both the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7 contained 25 cell groups, but the numbers of cells in each cell group between the two kinds of tissue were different. Genes PDGFRα, platelet endothelial cell adhesion molecule 1, lymphatic endothelial hyaluronic acid receptor 1, receptor protein tyrosine phosphatase C, keratin 10, and keratin 79 all had distinct distributions on two-dimensional tSNE plots, indicating specific cell groups respectively. The 25 cell groups were numbered by C0-C24 and divided into 9 dFb subgroups and 16 non-dFb groups. dFb subgroups included C0 as interstitial progenitor cells, C5 as adipose precursor cells, and C13 as contractile muscle cells related fibroblasts, etc. Non-dFb group included C3 as neutrophils, C8 as T cells, and C18 as erythrocytes, etc. Compared with that of the normal skin tissue of healthy mice, the intercellular communication in the wound tissue of full-thickness skin defected mice on PID 7 was more and denser, and the top 3 cell groups in intercellular communication intensity were dFb subgroups C0, C1, and C2, of which all communicated with other cell groups in the wound tissue. In the wound tissue of full-thickness skin defected mice on PID 7, VEGF signals were mainly sent by the dFb subgroup C0 and received by vascular related cell groups C19 and C21, PDGF signals were mainly sent by peripheral cells C14 and received by multiple dFb subgroups, EGF signals were mainly sent by keratinocyte subgroups C9 and C11 and received by the dFb subgroup C0, and the main sender and receiver of FGF signals were the dFb subgroup C6. In the relative contribution rank of FGF ligand receptor pairs to FGF signal network in the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7, FGF7-FGFR1 was the top 1, and FGF7-FGFR2 or FGF10-FGFR1 was in the second place, respectively; compared with those in the normal skin tissue, there was more intercellular communication in FGF7-FGFR1 signal pathway, while the intercellular communication in FGF7-FGFR2 and FGF10-FGFR1 signal pathways decreased slightly or did not change significantly in the wound tissue; the intercellular communication in FGF7-FGFR1 signal pathway in the wound tissue was stronger than that in FGF7-FGFR2 or FGF10-FGFR1 signal pathway; in the two kinds of tissue, FGF7 signal was mainly sent by dFb subgroups C0, C1, and C2, and received by dFb subgroups C6 and C7. Compared with that in the normal skin tissue of healthy mouse, the expression of FGF7 protein was higher in the wound tissue of full-thickness skin defected mouse on PID 7; in the normal skin tissue, FGF7 protein was mainly expressed in the skin interstitium and also expressed in the white adipose tissue near the dermis layer; in the two kinds of tissue, FGF7 protein was co-localized with DPP4 and SCA1 proteins and expressed in the skin interstitium, co-localized with PDGFRα protein and expressed in dFbs, but was not co-localized with SMA protein, with more co-localized expression of FGF7 in the wound tissue than that in the normal skin tissue. Conclusions: In the process of wound healing of mouse full-thickness skin defect wound, dFbs are highly heterogeneous, act as potential major secretory or receiving cell populations of a variety of growth factors, and have a close and complex relationship with the growth factor signal pathways. FGF7-FGFR1 signal pathway is the main FGF signal pathway in the process of wound healing, which targets and regulates multiple dFb subgroups.

Synthesis and characterization of chitosan-PVA hydrogel containing PEGylated recombinant epidermal growth factor on cell culture for wound healing substitute

Abstract The aim of the current study was to assess the physicochemical characteristics and wound healing activity of chitosan-polyvinyl alcohol (PVA) crosslinked hydrogel containing recombinant human epidermal growth factor (rh-EGF) or recombinant mouse epidermal growth factor (rm-EGF). The hydrogels were prepared and analyses were made of the morphological properties, viscosity, water absorption capacity, mechanical and bio-adhesive properties. The viscosity of the formulations varied between 14.400 - 48.500 cPs, with the greatest viscosity values determined in K2 formulation. F2 formulation showed the highest water absorption capacity. According to the studies of the mechanical properties, H2 formulation (0.153±0.018 N.mm) showed the greatest adhesiveness and E2 (0.245±0.001 mj/cm2) formulation, the highest bio-adhesion values. Hydrogels were cytocompatible considering in vitro cell viability values of over 76% on human keratinocyte cells (HaCaT, CVCL-0038) and of over 84% on human fibroblast cells (NIH 3T3, CRL-1658) used as a model cell line. According to the BrdU cell proliferation results, B1 (197.82±2.48%) formulation showed the greatest NIH 3T3 and C1 (167.43±5.89%) formulation exhibited the highest HaCaT cell proliferation ability. In addition, the scratch closure assay was performed to assess the wound healing efficiency of formulation and the results obtained in the study showed that F2 formulation including PEGylated rh-EGF had a highly effective role.

La importancia de la determinación del HER2 en el cáncer gástrico avanzado: a propósito de un caso clínico / Importance of HER2 status determination in advanced gastric cancer: A case study

Resumen El cáncer gástrico avanzado es una entidad que incluye dos situaciones clínicas distintas: el cáncer gástrico localmente avanzado no resecable y la enfermedad metastásica, cuyo tratamiento estándar es la quimioterapia. La sobreexpresión del receptor 2 del factor de crecimiento epidérmico humano (HER2) se puede presentar en esta enfermedad de un 9 % a un 38 % y ha sido el primer biomarcador predictivo utilizado para el tratamiento dirigido con trastuzumab en pacientes con tumores gástricos y de la región gastroesofágica avanzados. Se presenta en este artículo el caso de un paciente con cáncer gástrico avanzado con HER2 positivo manejado con quimioterapia convencional más trastuzumab como terapia blanco con adecuada respuesta clínica.

Abstract Advanced gastric cancer (AGC) is an entity that encompasses two distinct clinical situations: locally advanced unresectable gastric cancer and metastatic disease, with chemotherapy as the standard treatment. HER2 overexpression can occur in 9% to 38% of the cases with this disease and has been the first predictive biomarker used for trastuzumab-targeted therapy in patients with advanced gastric and gastroesophageal tumors. This article presents a patient with AGC and positive HER2 treated with conventional chemotherapy plus trastuzumab as targeted therapy with adequate clinical response.

The effect of epidermal growth factor on the pseudo-healing of traumatic tympanic membrane perforations / Efeito do fator de crescimento epidérmico na pseudocicatrização de perfurações traumáticas da membrana timpânica

Abstract Introduction: Traumatic tympanic membrane perforations tend to heal spontaneously. However, in this study, several perforations exhibited abnormal healing, where the morphology of healing tympanic membranes differed from that of non-perforated tympanic membranes. Pseudo-healing of the tympanic membrane was characterized by the accumulation of thickened tissue in the perforated area. Objective: The purpose of this study was to evaluate the utility of epidermal growth factor in cases showing pseudo-healing of traumatic tympanic membrane perforations. Methods: A total of 26 traumatic tympanic membrane perforations showing pseudo-healing were included in this study. In all cases, tissue that accumulated in the perforated area was removed, which subsequently caused a new perforation to form. An epidermal growth factor solution was applied to the tympanic membrane once daily to keep the tympanic membrane moist. Closure rates and times were evaluated at 6 months. Results: During the 6 months follow-up period, two patients were lost. Of the remaining 24 patients, the closure rate was 100% (24/24) and the closure time was 6.1 ± 2.3 days (range: 3-12 days). The morphology of the healed tympanic membrane was not significantly different from that of the remnant tympanic membrane. Conclusions: Pseudo-healing of traumatic tympanic membrane perforations affects sound conduction. This can be associated with various symptoms, including tinnitus, aural fullness, and ear discomfort. The excision of excessive epithelial tissue and topical application of epidermal growth factor can correct the pseudo-healing of traumatic tympanic membrane perforations.

Resumo Introdução: As perfurações traumáticas da membrana timpânica tendem a cicatrizar espontaneamente. Entretanto, neste estudo, várias perfurações exibiram cicatrização anormal, na qual a morfologia da cicatrização das membranas timpânicas diferiu da de membranas timpânicas não perfuradas. A pseudocicatrização da membrana timpânica foi caracterizada pelo acúmulo de tecido espesso na área perfurada. Objetivo: Avaliar a utilidade do fator de crescimento epidérmico em casos que apresentaram pseudocicatrização de perfurações traumáticas da membrana timpânica. Método: Um total de 26 casos de perfurações traumáticas da membrana timpânica apresentando pseudocicatrização foram incluídos neste estudo.. Em todos os casos, o tecido que se acumulou na área perfurada foi removido, o que subsequentemente causou uma nova perfuração. Uma solução de fator de crescimento epidérmico foi aplicada à membrana timpânica uma vez ao dia para manter a membrana timpânica úmida. As taxas de fechamento e os tempos foram avaliados aos 6 meses. Resultados: Dois pacientes foram perdidos no período de 6 meses de acompanhamento. Dos 24 pacientes restantes, a taxa de fechamento foi de 100% (24/24) e o tempo de fechamento foi de 6,1 ± 2,3 dias (variação: 3 a 12 dias). A morfologia da membrana timpânica cicatrizada não foi significativamente diferente daquela da membrana timpânica remanescente. Conclusões: A pseudocicatrização de perfurações traumáticas da membrana timpânica afeta a condução do som. Isso pode estar associado a vários sintomas, inclusive zumbido, plenitude aural e desconforto auditivo. A excisão do tecido epitelial excessivo e a aplicação tópica de fator de crescimento epidérmico podem corrigir a pseudocicatrização de perfurações traumáticas da membrana timpânica.

An epidermal growth factor motif of developmental endothelial locus 1 protein inhibits efficient angiogenesis in explanted squamous cell carcinoma in vivo

ABSTRACT Background: Cancer gene therapy using a nonviral vector is expected to be repeatable, safe, and inexpensive, and to have long-term effectiveness. Gene therapy using the E3 and C1 (E3C1) domain of developmental endothelial locus-1 (Del1) has been shown to improve prognosis in a mouse transplanted tumor model. Objective: In this study, we examined how this treatment affects angiogenesis in mouse transplanted tumors. Materials and methods: Mouse transplanted tumors (SCCKN human squamous carcinoma cell line) were injected locally with a nonviral plasmid vector encoding E3C1 weekly. Histochemical analysis of the transplanted tumors was then performed to assess the effects of E3C1 on prognosis. Results: All mice in the control group had died or reached an endpoint within 39 days. In contrast, one of ten mice in the E3C1 group had died by day 39, and eight of ten had died or reached an endpoint by day 120 (p < 0.01). Enhanced apoptosis in tumor stroma was seen on histochemical analyses, as was inhibited tumor angiogenesis in E3C1-treated mice. In addition, western blot analysis showed decreases in active Notch and HEY1 proteins. Conclusion: These findings indicate that cancer gene therapy using a nonviral vector encoding E3C1 significantly improved life-span by inhibiting tumor angiogenesis. (REV INVEST CLIN. 2021;73(1):39-51)

Role of metabolic reprogramming in drug resistance to epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer / 中南大学学报(医学版)

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can effectively inhibit the growth of EGFR-dependent mutant non-small cell lung cancer (NSCLC). Unfortunately, NSCLC patients often develop severe drug resistance after long-term EGFR-TKI treatment. Studies have shown that the disorder of energy metabolism in tumor cells can induce EGFR-TKI resistance. Due to the drug action, gene mutation and other factors, tumor cells undergo metabolic reprogramming, which increases the metabolic rate and intensity of tumor cells, promotes the intake and synthesis of nutrients (such as sugar, fat and glutamine), forms a microenvironment conducive to tumor growth, enhances the bypass activation, phenotype transformation and abnormal proliferation of tumor cells, and inhibits the activity of immune cells and apoptosis of tumor cells, ultimately leading to drug resistance of tumor cells to EGFR-TKI. Therefore, targeting energy metabolism of NSCLC may be a potential way to alleviate TKI resistance.

Cytoplasmic-membrane egfr predicts expanded ras mutation status in colorectal carcinomas? / Egfr membrano-citoplasmático prediz mutação ras expandida no carcinoma colorretal?

ABSTRACT Background: Inhibitors of the epidermal growth factor (EGFR) represent an effective therapeutic option for patients with metastatic colorectal carcinoma, free of activating mutations in KRAS and NRAS. However, the research of mutations is of high cost and scarcely accessible. The expression of the EGFR by immunohistochemistry predicting the mutation status of the expanded RAS (KRAS and NRAS), may allow treatment by a diagnostic method less costly and more accessible. Aim: Investigate the correlation between the clinical-pathological data, the cytoplasmic-membrane expression of the EGFR and the mutational status of the expanded RAS. Method: A total of 139 patients with colorectal carcinoma from the archives of Instituto Goiano de Oncologia e Hematologia were evaluated. Results: Mutation of the expanded RAS was detected in 78 (56.1%) cases. The EGFR expression was stratified in 23 (16.5%) "positive", 49 (35.2%) "negative" and 67 (48.2%) "uncertain". No significant correlation was found between the mutational status of the RAS and the EGFR expression in comparison to age, gender, location, histological type, histological grade and stage. From 23 "positive" cases, 21 (91.3%) showed wild-type RAS gene, and 49 "negative", 41 (83.7%) presented mutation, resulting in a strong association between EGFR "positive", "negative" groups and the mutational status of the RAS (p<0.001), with 86.1% of accuracy. Conclusions: The cytoplasmic-membrane analysis of the EGFR expression stratified into "positive", "negative" and "uncertain" predicts mutational status of the RAS in 51.7% of the cases (p<0.001), with 86.1% of accuracy.

RESUMO Racional: Inibidores do fator de crescimento epidermal (EGFR) representam opção de terapia efetiva para o câncer colorrectal metastático, na ausência de ativação de mutações KRAS e NRAS. Entretanto, a pesquisa de mutações é cara e pouco acessível. A expressão de EGFR por imuno-histoquímica predizendo o status mutacional do RAS expandido (KRAS e NRAS) poderia permitir o tratamento por método diagnóstico menos caro e mais acessível. Objetivo: Investigar a correlação entre os dados clinicopatológicos, a expressão de EGFR na membrana citoplasmática e o status mutacional do RAS expandido. Método: Estudo retrospectivo de acurácia envolvendo 139 pacientes com carcinoma colorretal. Resultado: A mutação do RAS expandido foi detectada em 78 (56,1%) casos. A expressão de EGFR foi estratificada em 23 (16,5%) casos "positivos", 49 (35,2%) casos "negativos" e 67 (48,2%) "duvidosos". Não houve correlação significante entre o status mutacional do RAS e a expressão de EGFR em relação a idade, gênero, local do tumor, tipo histológico, grau histológico e estádio clínico. Em 23 casos "positivos", 21 (91,3%) mostraram gene RAS tipo selvagem, e em 49 "negativos", 41 (83,7%) apresentaram mutação, resultando em forte associação entre grupos EGFR "positivo" ou "negativo" e o status mutacional do RAS (p<0.001), com 86,1% de acurácia. Conclusão: A análise da expressão de EGFR na membrana citoplasmática estratificada em "positivo", "negativo" e "duvidoso" prediz o status mutacional do RAS em 51,7% dos casos (p<0.001), com 86,1% de acurácia.

Salivary molecules of bone remodeling and tissue repair after head and neck radiotherapy

Abstract Head and neck radiotherapy causes quantitative and qualitative changes in saliva. The objective of this case-control study was to evaluate the salivary biomarkers associated with bone remodeling and tissue repair in patients submitted to radiotherapy for head and neck cancer treatment, compared with non-irradiated individuals. Total unstimulated saliva was collected for ELISA assay analysis of receptor activator for nuclear factor κ B (RANK) and its ligand (RANK-L), osteoprotegerin, matrix metalloproteinase-9/ tissue inhibitor of metalloproteinase-2, vascular endothelial growth factor, and epidermal growth factor. Statistics were performed, and revealed that salivary RANK (p = 0.0304), RANK-L (p = 0.0005), matrix metalloproteinase-9/ tissue inhibitor of metalloproteinase-2 (p = 0.0067), vascular endothelial growth factor (p = 0.0060), and epidermal growth factor (p < 0.0001) were reduced in patients, compared with the control group. Osteoprotegerin did not differ between the groups (p = 0.3765). Salivary biomarkers did not differ according to radiotherapy completion time (p > 0.05). In conclusion, the lower output of the salivary molecules - essential for bone remodeling and tissue repair - may disrupt tissue homeostasis and play a role in the pathogenesis of the radiotherapy-induced deleterious effects in the oral cavity.

Efectos del Factor de crecimiento epidérmico sobre las características histológicas del riñón en ratas con Insuficiencia renal crónica / Effects of Epidermal growth factor on histological features of the kidney in rats with Chronic kidney failure

Introducción: la Insuficiencia renal crónica es un problema de salud pública, por lo que surge la necesidad de incrementar las acciones dirigidas a su prevención, diagnóstico e intervenciones terapéuticas eficaces; estudios recientes emplean el Factor de crecimiento epidérmico para evaluar su efecto reno-protector en variables funcionales; sin embargo se carece de estudios relacionados con los efectos de este producto sobre las características histológicas de riñones insuficientes. Objetivo: determinar los posibles efectos protectores y/o reparadores del Factor de crecimiento epidérmico humano recombinante sobre las características histológicas de riñones con insuficiencia renal crónica. Material y métodos: se trabajó con tres series, formadas por un grupo control y uno experimental cada una, de cinco animales, a los grupos experimentales se les realizó ablación quirúrgica de 5/6 de la masa renal. La serie A se conformó por animales controles, la B por los tratados con Factor de crecimiento epidérmico 24 horas antes del procedimiento y la C por los tratados con el bioproducto 24 horas después. Pasados 56 días del acto operatorio a los animales se les practicó la eutanasia y se procedió al estudio histológico del riñón. Resultados: en los animales de la serie A se observaron alteraciones histológicas en los corpúsculos y túbulos renales, en la serie B se observó que la mayor parte del parénquima renal presentó características normales y los de la serie C mostraron un daño renal incrementado. Conclusiones: El Factor de crecimiento epidérmico humano recombinante posee efecto reno-protector, sin embargo, no ofrece efecto reno-reparador(AU)

Introduction: Chronic Kidney Failure is a public health problem; therefore, the need for actions aimed at its prevention, diagnosis and effective therapeutic interventions is a most. Recent studies use the Epidermal Growth Factor to evaluate its reno-protective effect on functional variables; however, there are no studies related to the effects of this product on histological features of kidney in chronic failure. Objective: To determine the possible protective and / or repair effects of recombinant human epidermal growth factor on the histological features of kidneys in chronic renal failure. Material and methods: We worked with three series, each consisting of a control group and an experimental group of five animals. The experimental groups underwent 5/6 surgical ablation of the renal mass. Series A consisted of control animals, series B included those animals treated with Epidermal Growth Factor 24 hours before the procedure and series C was made up of those animals treated with the bioproduct 24 hours after the procedure. Fifty-six days after surgical act, euthanasia was practiced on the animals and the kidneys were histologically studied. Results: Histological alterations were observed in the renal corpuscles and tubules in the animals included in series A; in series B it was observed that most of the renal parenchyma presented normal characteristics and those in series C showed increased kidney damage. Conclusions: Recombinant human epidermal growth factor has a reno-protective effect; however, it does not offer a repair effect of acute kidney(AU)

Analysis of Tau Protein Expression in Predicting Pathological Complete Response to Neoadjuvant Chemotherapy in Different Molecular Subtypes of Breast Cancer / 한국유방암학회지

PURPOSE: Tau is a microtubule-associated protein that can be found in both normal and abnormal breast cells. Whether the expression of Tau protein can predict the response to neoadjuvant chemotherapy (NACT) is still unclear. In this study, we assessed the role of Tau protein expression in predicting a pathological complete response (pCR) to NACT for different subtypes of breast cancer.METHODS: Four hundred and sixty-eight eligible patients were retrospectively recruited in our study. The relationship between clinicopathologic factors, including Tau protein expression, and pCR in different subtypes was evaluated using logistic regression analysis. Correlation between Tau and disease-free survival (DFS) and overall survival (OS) was performed using Kaplan–Meier analysis.RESULTS: The expression of Tau protein was negatively correlated with pCR, especially in triple-negative breast cancer (TNBC). No significant difference was observed in the luminal human epidermal growth factor receptor-2 (HER2)-negative subtype and HER2-positive subtype. Patients with pCR were associated with better DFS and OS (p < 0.05). However, Tau protein expression had no association with either DFS or OS (p > 0.05).CONCLUSION: Tau protein expression can predict pCR before NACT in TNBC, but there was no correlation between Tau expression and DFS or OS.

Progress in human epidermal growth factor research / 生物工程学报

Human epidermal growth factor (hEGF) is a typical member of the growth factor family that activates epidermal growth factor receptors. It is synthesized and secreted by multiple tissues and organs of the human body, regulating the cell proliferation, differentiation and migration via binding to receptors and activating a series of signaling pathways. In recent years, the research on hEGF has been extended to its role in human physiology and pathology, especially in tissue regeneration and wound healing. This paper reviews the research progress of hEGF, briefly describes its gene and protein structure and characteristics, mechanisms and biological effects, with the emphasis on the roles and influences in the healing of gastrointestinal ulcers, skin wound repair and tumor pathology.

Impact of Kuntai Capsules on LIF, IGF-1 and EGF expression in the implantation window of endometrium in mice / Impacto de cápsulas de Kuntai en la expresión de LIF, IGF-1 y EGF en la ventana de implantación de endometrio en ratones

To investigate the influence of Kuntai capsules on the expression level of leukemia inhibitory factor (LIF), insulin-like growth factor-I (IGF-1)and epidermal growth factor (EGF) during the mouse's implantation window of superovulation period and controlled ovarian hyperstimulation period. 90 female mice were randomly divided into six groups in control, superovulation and controlled ovarian hyperstimulation (COH) conditions. The RNA expression of EGF, LIF and IGF-1 in the endometrium on the 4th day of pregnancy was detected, and the relative expression was compared. mRNA expression of these three factors in endometrium was significantly lower in superovulation and COH groups than control group (p<0.001). mRNA expression of these three factors in endometrium remained obviously lower in superovulation plus kuntai capsule group and COH plus kuntai capsule group than control group (p<0.01). mRNA expression of these three factors in endometrium was lower in control group than in the NS plus kuntai capsule group (p<0.05). Kuntai capsule cannot completely reverse the endometrial damages caused by superovulation and COH. Thus Kuntai capsule could partially improve a mouse's endometrial receptivity during the implantation window.

Para investigar la influencia de las cápsulas de Kuntai en el nivel de expresión del factor inhibidor de la leucemia (LIF), el factor de crecimiento similar a la insulina I (IGF-1) y el factor de crecimiento epidérmico (EGF) durante la ventana de implantación del ratón del período de superovulación y la hiperestimulación ovárica controlada período, se dividieron aleatoriamente 90 ratones hembra en seis grupos en condiciones de control, superovulación e hiperestimulación ovárica controlada (COH). Se detectó la expresión de ARN de EGF, LIF e IGF-1en el endometrio al cuarto día de embarazo, y se comparó la expresión relativa. La expresión de ARNm de estos tres factores en el endometrio fue significativamente menor en los grupos de superovulación y COH que en el grupo control (p<0,001). La expresión de ARNm de estos tres factores en el endometrio permaneció más baja en el grupo de cápsulas de superovulación más Kuntai y en el grupo de cápsulas de COH más Kuntai respecto del grupo control (p<0,01). La expresión de ARNm de estos tres factores en el endometrio fue menor en el grupo control que en el grupo de cápsula NS más Kuntai (p<0,05). La cápsula de Kuntai no pudo revertir completamente los daños endometriales causados por la superovulación y la COH. Por lo tanto, se sugiere que la cápsula de Kuntai podría mejorar parcialmente la receptividad endometrial de un ratón durante la ventana de implantación.

Fatores de crescimento e cicatrização: experiência em um serviço de Dermatologia / Growth factors and healing: experience in a Dermatology service

Introdução: A cicatrização é um fenômeno que ocorre após lesão tecidual e envolve mecanismos celulares e moleculares complexos. Os fatores de crescimento parecem ser um complemento eficaz e seguro no tratamento das feridas. Objetivo: Avaliar a cicatrização de feridas após eletrocoagulação, comparando-se o veículo isolado à sua associação com o fator de crescimento epidérmico. Métodos: Ensaio clínico duplo-cego em Serviço de Dermatologia entre 2016 e 2018. Incluídos pacientes de ambos os sexos, acima de 18 anos, submetidos à eletrocoagulação de duas lesões e posterior aplicação de veículo (cold cream) em uma e fator de crescimento epidermico em cold cream na outra. Avaliações com sete, 14 e 28 dias, analisaram: eritema, edema, crosta, secreção e cicatrização. Utilizou-se o teste binomial para duas proporções e o teste exato de Fisher para dados dicotômicos. Resultados: Em relação a eritema, edema, crosta e secreção foram encontrados resultados variáveis, ora favorecendo o veículo, ora o fator de crescimento, porém sem significância estatística. Quanto à cicatrização, a epitelização mostrou-se mais rápida com fator de crescimento epidermico (p<0,05). Conclusões: Os resultados deste estudo, que avaliou o impacto do fator de crescimento epidérmico no processo de cicatrização, corroboram os dados da escassa literatura atual e servem de base para estudos futuros.

Introduction: Healing is a phenomenon that occurs after tissue injury and involves complex cellular and molecular mechanisms. Growth factors seem to be an effective and safe complement for the treatment of wounds. Objective: To evaluate wound healing after electrocoagulation, comparing the vehicle in isolation and its association with epidermal growth factor. Methods: Double-blind clinical trial in a Dermatology service between 2016 and 2018. Patients of both genders, older than 18 years of age, submitted to electrocoagulation of two lesions and subsequent application of the vehicle (cold cream) on one and epidermal growth factor in cold cream on the other were included. Evaluations after 7, 14 and 28 days, analysed erythema, edema, crusting, discharge and healing. Analyzed: edema, edema, crusting, discharge and healing. The binomial test was used for two ratios and Fisher's exact test was used for dichotomic data. Results: Variable results were found regarding erythema, edema, crusting and discharge, sometimes favoring the vehicle, sometimes the growth factor, however with no statistical significance. Regarding healing, epithelialization was quicker with epidermal growth factor (p<0.05). Conclusions: This study evaluated the impact of epidermal growth factor in the healing process, and its results reinforce scarce data of the current literature and are a foundation for future studies.

Comparison of cobas EGFR Mutation Test v2 and PANAMutyper-R-EGFR for Detection and Semi-Quantification of Epidermal Growth Factor Receptor Mutations in Plasma and Pleural Effusion Supernatant

BACKGROUND: Plasma epidermal growth factor receptor (EGFR) mutation tests are less invasive than tissue EGFR mutation tests. We determined which of two kits is more efficient: cobas EGFR Mutation test v2 (cobasv2; Roche Molecular Systems, Pleasanton, CA, USA) or PANAMutyper-R-EGFR (Mutyper; Panagene, Daejeon, Korea). We also evaluated whether pleural effusion supernatant (PE-SUP) samples are assayable, similar to plasma samples, using these two kits. METHODS: We analyzed 156 plasma and PE-SUP samples (31 paired samples) from 116 individuals. We compared the kits in terms of accuracy, assessed genotype concordance (weighted κ with 95% confidence intervals), and calculated Spearman's rho between semi-quantitatively measured EGFR-mutant levels (SQIs) measured by each kit. We also compared sensitivity using 47 EGFR-mutant harboring samples divided into more-dilute and less-dilute samples (dilution ratio: ≥ or <1:1,000). RESULTS: cobasv2 tended to have higher accuracy than Mutyper (73% vs 69%, P=0.53), and PE-SUP samples had significantly higher accuracy than plasma samples (97% vs 55–71%) for both kits. Genotype concordance was 98% (κ=0.92, 0.88–0.96). SQIs showed strong positive correlations (P<0.0001). In less-dilute samples, accuracy and sensitivity did not differ significantly between kits. In more-dilute samples, cobasv2 tended to have higher sensitivity than Mutyper (43% vs 20%, P=0.07). CONCLUSIONS: The kits have similar performance in terms of EGFR mutation detection and semi-quantification in plasma and PE-SUP samples. cobasv2 tends to outperform Mutyper in detecting less-abundant EGFR-mutants. PE-SUP samples are assayable using either kit.

Overexpression of HER2/HER3 and clinical feature of ovarian cancer / 부인종양

OBJECTIVES: Human epidermal growth factor receptor-2 (HER2) and 3 (HER3) belong to the epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases. In this study, we assessed HER2/HER3 expression levels in specimens of epithelial ovarian cancer and determined their correlation with clinical features of ovarian cancer. METHODS: Tissue microarrays (TMAs) were prepared from paraffin blocks of 105 ovarian tumour samples. HER2, HER3, PI3K, Akt, p-Akt, mTOR, p-mTOR, S6, and p-S6 expression levels were investigated using immunohistochemistry (IHC). HER2 and HER3 amplifications were determined using in situ hybridization (ISH). The correlation between HER2/3 expression and disease outcome of the patients including surgical outcome, progression-free survival (PFS) and overall survival (OS) was analysed. RESULTS: HER2 positivity was 3.8% by IHC and 5.7% by ISH, whereas that of HER3 was 12.4% and 8.6%, respectively. HER2 status by either IHC or ISH was not related to PFS (p=0.128, 0.168, respectively) and OS (p=0.245, 0.164, respectively). However, the HER3 status determined using fluorescence ISH was associated with poor PFS (p=0.035 on log rank test), which was a significant risk factor even after adjusting other possible risk factors in multivariate analysis (hazard ratio=2.377 [1.18–7.49], p=0.021). Expressions of Akt, p-mTOR, and S6 were also related with poor progression (p=0.008, 0.049, 0.014, respectively). CONCLUSION: HER3 is possibly an independent marker for poor prognosis in individuals with ovarian cancer, as the HER3 signalling pathway is distinct from that of HER2. The possibility of targeted therapy for patients with HER3 alteration in ovarian cancer should be evaluated.