Serum Epidermal Growth Factor Research Articles

Clinical significance of serum epidermal growth factor receptor (EGFR) levels in patients with breast cancer

Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of multiple malignancies and its expression strongly also affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of EGFR in breast cancer (BC) patients. A total of 96 patients with a pathologically confirmed diagnosis of BC were enrolled into this study. Serum EGFR levels were determined by the solid-phase sandwich ELISA method. Age and sex matched 30 healthy controls were included in the analysis. Median age of diagnosis was 48years old (range: 29–80). Thirty-seven (39%) consisted of metastatic disease. The baseline serum EGFR levels were significantly higher than in the healthy control group (p<0.001). The serum EGFR concentrations were also significantly higher only in patients with ER-negative and triple-negative tumor (p=0.05 and p=0.04, respectively). The other known clinical variables, including grade of histology, stage of disease, serum CA 15.3 levels, and response to chemotherapy were not found to be correlated with serum EGFR concentrations (p>0.05). Likewise, serum EGFR levels were found to play no prognostic role for survival (p=0.35). In conclusion, while serum EGFR levels were elevated in BC patients, EGFR level has no predictive and prognostic value in these patients.

Relationship between serum carcinoembryonic antigen level and epidermal growth factor receptor mutations and prognosis in resected non-small cell lung cancer

Relationship between serum carcinoembryonic antigen level and epidermal growth factor receptor mutations and prognosis in resected non-small cell lung cancer

Impact of epidermal growth factor single‐nucleotide polymorphism on recurrence of hepatocellular carcinoma after hepatectomy in patients with chronic hepatitis C virus infection

Epidermal growth factor (EGF) gene single-nucleotide polymorphism (SNP) is associated with an increased risk of hepatic tumors. The study aimed to elucidate the impact of EGF SNP and EGF receptor (EGFR) expression on the recurrence of hepatocellular carcinoma (HCC) after hepatectomy. To examine the impact of EGF SNP and EGFR on recurrent HCC, we retrospectively analyzed 141 HCC patients with chronic hepatitis C virus infection who underwent curative hepatectomy. The EGF *61 GG allele was present in 69 patients (48.9%), AG in 56 (39.7%) and AA in 16 (11.4%). The AA group had a significantly lower rate of intrahepatic metastasis (0% vs 16.5%, P = 0.02), lower serum EGF concentration (26.3 ± 15.9 pg/mL vs 43.4 ± 30.5 pg/mL, P = 0.02) and lower proportion of early recurrence (≤2 years; 28.6% vs 71.2%, P = 0.03) than the AG/GG group. The AA group had significantly higher recurrence-free survival than the AG/GG group (P = 0.04), but there was no significant difference in overall survival between these two groups (P = 0.97). High versus low EGFR expression analyzed by immunohistochemical staining in cancer cells was not significantly associated with overall survival (P = 0.37) or recurrence-free survival (P = 0.39). Therefore, EGF *61 AA was associated with a lower risk of recurrence after curative hepatectomy for HCC in patients with hepatitis C virus infection than other genotypes, but EGFR expression in cancer cells was not significantly associated with prognosis.

Effect of psoriasis activity on epidermal growth factor (EGF) and the concentration of soluble EGF receptor in serum and plaque scales.

Epidermal growth factor receptors (EGFRs) are overexpressed in psoriatic keratinocytes, and regulate cell growth, proliferation and differentiation through binding to epidermal growth factor (EGF). The role of EGF and EGFRs in the pathogenesis of psoriasis and the contribution of their measurement to psoriasis management are still unknown. To evaluate serum concentrations of EGF, soluble (s)EGFRs and EGF content in psoriatic scales of patients with severe psoriasis, and to analyse their association with the clinical activity of the disease. Serum samples and plaque scales were collected from 51 patients with plaque-type psoriasis. Concentrations of EGF and sEGFR in serum and of EGF in scales were measured using enzyme immunoassay. Data were analysed with respect to baseline Psoriasis Area and Severity Index (PASI). Mean serum EGF concentration in patients was higher than in controls (701±72 vs. 586±63pg/mL), but the difference was not significant. Mean serum concentration of sEGFR was significantly lower than controls (40.8±1.4 vs. 86.4±11.3ng/mL, P<0.001). Serum levels of EGF showed a significant positive correlation and EGFR showed a significant negative correlation with PASI (P<0.05). No correlation was seen between PASI and EGF content in scales or between EGF and sEGFR levels. Serum EGF concentrations reached the highest mean level (914±138pg/mL) in patients with PASI>20, and this was significantly higher than the mean of 414±82pg/mL in the group with PASI<10. Mean sEGFR serum concentrations remained significantly lower than those of controls, irrespective of disease severity. Compared with controls, patients with psoriasis had increased EGF and decreased sEGFR levels in serum. EGF and sEGFR levels correlated with disease severity.

Correlations between Carcinoembryonic Antigen, Epidermal Growth Factor and Leptin in Patients with Non-Small-Cell Lung Cancer

Objectives:Carcinoembryonic antigen (CEA), epidermal growth factor (EGF) and leptin have been reported to be intimately intertwined in lung carcinogenesis.However, few studies have simultaneously examined these proteins in lung cancer and whether a correlation exist among them remains unclear. Here, we compared the levels of CEA, EGF and leptin in non-small-cell lung cancer (NSCLC) patients and controls and evaluated the possible associations among them. Methods:97 patients ranged from 30 to 83 years of age were studied. Serum CEA, EGF and leptin levels were determined following a standard protocol. The relationships between these proteins and clinicopathological factors were evaluated by Wilcoxon rank sum or Kruskal-Wallis H test. Spearman rank-correlation were used to determine the correlations among CEA, EGF and leptin. Co-expression of these proteins in NSCLC tissues was examined by immunofluorescence. Results: Serum CEA and leptin levels in NSCLC patients were significantly higher compared to controls (both P = 0.000), but no statistically significant difference was found for EGF. CEA and EGF were not associated with the tumor-related factors, but leptin was strongly correlated with sex (P = 0.005). Significant correlations among these proteins were found when the patients were categorized into subgroups. Co-expresstion of these proteins was significantly enhanced with lung carcinogenesis. Conclusions:CEA, EGF and leptin may interplay and play vital roles in the pathogenesis of NSCLC. Besides CEA, the leptin levels were also significantly higher in NSCLC patients than in controls. Determination of preoperative leptin levels may prove useful for screening and predicting NSCLC.

Treatment for salivary gland hypofunction at both initial and advanced stages of Sjögren-like disease: a comparative study of bone marrow therapy versus spleen cell therapy with a 1-year monitoring period

Background aimsNon-obese diabetic mice (NOD) exhibit autoimmune Sjögren-like disease (SS-like). We reported previously that a combined-therapy consisting of immuno- and cell-based therapy rescued NOD from SS-like. However, therapies tested to date on NOD mice were aimed at the initial phase of SS-like. It is unknown whether therapies are effective in restoring salivary function when given at an advanced phase of SS-like. MethodsThe efficacy of two therapies (bone marrow versus spleen cells) was compared head-to-head for halting/reversing salivary hypofunction at two critical time points of SS-like (7-week-old NOD with normal saliva output and 20-week-old NOD with minimal saliva). NOD mice were divided into four groups: (i) control, (ii) complete Freund's adjuvant (CFA), (iii) bone marrow transplants with CFA or (iv) spleen cell transplants with CFA. Mice were monitored 8–12 months after therapy. ResultsBoth cell therapies were effective during the initial phase of SS-like; salivary flow rates were maintained between 80–100% of pre-symptomatic levels. Spleen cell therapy was better than bone marrow when administered in the initial phase of SS-like. When cell therapies were given at an advanced phase of SS-like (20 weeks and older), salivary flow rates improved but were at best 50% of pre-symptomatic levels. Both cell therapies decreased tumor necrosis factor-α, transforming growth factor-β1 levels and T and B cells while increasing epidermal growth factor and regulatory T cells. Elevated serum epidermal growth factor levels were measured in spleen-treated mice. ConclusionsA therapeutic effect in advanced phase disease, albeit in mice, holds promise for humans in which Sjögren syndrome is generally not diagnosed until a late stage.

Immunoregulatory role of Pleurotus eryngii superfine powder through intercellular communication of cytokines

Pleurotus eryngii, also known as thistle mushroom, is rich in proteins, dietary fibre and polysaccharides. It has been developed as a functional food due to its antioxidant, anti-fatigue, anti-viral and anti-tumour functions. The objective of this study was to investigate the mechanisms of the immunoregulatory and antioxidant effects of P. eryngii superfine powder (PESP) in vivo. Test mice were fed with a diet containing 6.67% PESP to explore its effect on mouse delayed-type hypersensitivity, phagocytic index, serum hemolysin, serum and liver glutathione peroxidase (GSH-PX) activities, serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in liver homogenate. For the human study, volunteers received PESP at doses of 5, 10 or 15 g. Serum levels of 39 cytokines were determined before and after ingestion using a Millipore Human Kit and a liquid chip scanner. Our results showed that, in mice, dietary P. eryngii supplementation significantly increased the weight difference of ears (P < 0.01), phagocytic index (P < 0.05), serum hemolysin (P < 0.01), serum and liver GSH-PX activities (P < 0.01) and serum SOD activity (P < 0.01), but decreased MDA content (P < 0.01) in liver homogenate. In human trials, 5 g of PESP significantly decreased serum epidermal growth factor, while 15 g of PESP significantly decreased serum granulocyte–macrophage colony stimulating factor, macrophage-derived chemokine and tumour necrosis factor-α. No change was detected in serum cytokines after the administration of 10 g of PESP. P. eryngii can regulate innate and acquired immune functions in mice to execute antioxidant and anti-aging functions, and can alter human serum cytokines. The dual immunoregulatory effects of P. eryngii are consistent with the theory of traditional Chinese medicine.

Serum epidermal growth factor is associated with prognosis and hormone receptor status in patients with HER2-positive metastatic breast cancer treated with first-line trastuzumab plus taxane chemotherapy

Epidermal growth factor (EGF) is a ligand for the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor 2 (HER2) shares common signal pathways and forms a heterodimer with EGFR. In this study, we investigated the clinical and pathologic implications of serum EGF levels in patients with HER2-positive metastatic breast cancer (MBC). We analyzed serum EGF levels from baseline serum samples of consecutive patients with HER2-positive MBC who received first-line trastuzumab plus taxane chemotherapy and correlated them with treatment outcomes and pathologic features. A total of 50 women were analyzed. The median age was 47 years (range 27-72 years). Patients with high serum EGF levels (≥10.0 pg/mL) had significantly longer overall survival (47.0 months (95 % confidence interval (CI) 28.3-65.7 months) vs. 23.3 months (95 % CI 13.5-33.1 months); p = 0.009) with a tendency toward longer progression-free survival (p = 0.123). Serum EGF levels were not associated with hematologic or cardiac adverse events. Progesterone receptor-positive patients had significantly higher serum EGF levels than progesterone receptor-negative patients (24.3 pg/mL (range 9.5-69.0 pg/mL) vs. 12.3 pg/mL (range 0.0-59.5 pg/mL); p = 0.006). Our data suggest that high serum EGF levels may be associated with good prognosis in patients with HER2-positive MBC receiving trastuzumab plus taxane chemotherapy. In addition, serum EGF levels were associated with progesterone receptor positivity.

62cuatsm and 62cuptsm PET is a useful imaging tool for hypoxia and perfusion in lung cancer.

e22166 Background: Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis (N4-methylthiosemicarbazone), CuATSM, have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another positron emission tomography (PET) imaging agent, copper-pyruvaldehyde-bis (N4-methylthiosemicarbazone), 62CuPTSM, which can detect areas of perfusion, can augment the information obtained in 62CuATSM PET scans. Methods: In order to characterize tumors based on both perfusion and hypoxia, ten patients were studied using both 62CuATSM and 62CuPTSM PET scans. All patients signed informed consent; the protocol was approved by the Duke University Medical Center institutional review board. 62CuATSM and 62CuPTSM SUV values at steady state were tabulated and the ratios of 62CuATSM to 62CuPTSM calculated. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed. Results: Six out of ten patients had fully evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using 62CuATSM/62CuPTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between serum epidermal growth factor (EGF) levels and 62CuATSM detected hypoxia. Conclusions: This initial series of 62CuATSM/62CuPTSM PET scans demonstrate that evaluating pulmonary lesions by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of 62CuATSM and 62CuPTSM PET imaging techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care.

Relationships between Pork Quality Traits and Growth Factor Concentrations in Serum and Longissimus dorsi Muscle before and at Slaughter in Female Market Pigs

The present study was conducted to test a hypothesis that pork quality traits would be influenced by the systemic and/or local bioavailability of insulin-like growth factor-I (IGF-I), transforming growth factor-β 1( TGF-β1), or epidermal growth factor (EGF) before or at slaughter. To this end, 60 cross-bred female market pigs weighing approximately 110 kg were slaughtered, after which Longissimus dorsi muscle (LM) samples taken at slaughter (D 0) and blood samples taken at D -7 and D 0 were analyzed. The 60 carcasses rendered 36 RFN (reddish-pink, firm, and non-exudative), 16 RSE (reddish-pink, soft, and exudative), and 6 PSE (pale, soft, and exudative); 2 DFD (dark, firm, and dry) also were found but were excluded in subsequent experiments. The L* and drip loss were greater in PSE vs. RFN and RSE and in PSE and RSE vs. RFN, respectively, as they should (P<0.05). The pH45min was less in PSE vs. RFN (P<0.05); pH24h tended to be less in the former (P=0.09). The LM IGF-I and TGF-β1 as well as serum EGF concentrations were less in PSE than in RFN. None of the other LM and serum concentrations of the three growth factors differed across the three pork quality categories. The LM IGF-I and TGF-β1 concentrations and serum EGF concentration at D 0 were negatively correlated with drip loss (r =-0.36(P<0.01), -0.44 (P<0.01), and -0.32 (P<0.05), respectively). However, none of the serum and LM growth factor variables was correlated with L* or a* (redness) of LM. Taken together, results suggest that locally expressed IGF-I and TGF-β1 and blood-borne EGF may have a beneficial effect on postmortem water holding capacity of the muscle and that pork quality traits could be predicted to some extent from concentrations of IGF-I and TGF-β1 in muscle and EGF in serum at slaughter.

Serum EGF and NGF levels of patients with brain injury and limb fracture

ObjectiveTo explore the expression and significance of human epidermal growth factor (EGF) and nerve growth factor (NGF) in patients with knee osteoarthritis. MethodsRT-PCR and enzyme-linked immunosorbent assay were used to measure the serum EGF and NGF expression levels of patients with limb fracture and brain trauma injurry after 1 d, 3 d, 7 d, 14 d and the relationship between them was analyzed. The level was compared among the simple fracture group, traumatic brain injury group and the normal control group, with 40 cases in each group. ResultsThe serum NGF levels were significantly different among three groups. Serum NGF, EGF mRNA and protein levels gradually decreased with the increasing injury time in the limb fracture combined with brain injury group, traumatic brain injury group, the simple fracture group and the health control group (P<0.05). ConclusionsThe serum of NGF, EGF levels significantly increased when limb fracture combined with brain injury, so EGF and NGF may be involved in the process of fracture healing.

Prognostic value of circulating cytokines in colon cancer recurrence

DOI of original article: 10.1016/j.jss.2012.0 * Corresponding author. Department of Surg 6609 E-mail address: harish.lavu@jefferson.ed 0022-4804/$ e see front matter a 2014 Elsev http://dx.doi.org/10.1016/j.jss.2013.02.004 Dr Lee and his colleagues at GachonUniversity have published an interesting study on the correlation between colon cancer outcomes and preoperative serum epidermal growth factor (EGF), C-reactive protein (CRP), and interleukin 6 (IL-6) levels in a stage III subpopulation [1]. The incidence of colon cancer has increased steadily in recent years and colon cancer now accounts for 15% of all cancer deaths worldwide [1,2]. Furthermore, although AJCC TNM stage classification has proven useful, it still has its limitations, due in part to the variance of patient outcomes within a given stage [2]. There is a necessity to develop accurate molecular markers to aid in predicting the risk of cancer recurrence in surgically treated patients, to more accurately identify those who will benefit from adjuvant treatment [1,2]. In this study, the authors analyzed the efficacy and use of EGF/EGF receptor, CRP, and IL-6 as markers for stage III colon cancer recurrence. In this prospective work, which took place between April 2008 and August 2009, the authors studied 77 patients with curatively resected stage III colon cancer at the Gil Cancer Center, Gil Hospital, Gachon University, Korea. Each case had a histologically confirmed diagnosis of colon adenocarcinoma, and serum samples of IL-6, CRP, and EGF were taken from the

Serum epidermal growth factor receptor levels in patients with malignant melanoma

Epidermal growth factor receptor (EGFR) is known to be abnormally expressed in many human carcinomas, suggesting that there may be an increase in serum EGFR levels in patients with malignant melanoma (MM) and that this might be a possible new tumour marker. To assess whether serum EGFR levels might be a marker of MM. Serum samples were obtained from 66 patients with MM and 12 healthy controls, and EGFR levels were measured by double-determinant ELISA. Patients with in situ or stage I MM had significantly higher serum EGFR levels compared with healthy controls. Interestingly, serum EGFR levels decreased gradually with the stage of the tumour, being highest at stage I and lowest at stage IV. There was also a trend towards a reverse correlation between tumour thickness and serum EGFR levels. Moreover, a longitudinal study identified a trend for serum EGFR levels in patients with preoperative MM to decrease compared with patients with recurrent MM. To our knowledge, this is the first report investigating the serum EGFR levels of patients with MM, and gives new insight into the relationship between EGFR and MM. We found that serum EGFR levels were significantly increased in patients with early-stage MM such as in situ and stage I tumours. Measurements of serum EGFR levels might be of clinical value in the detection of early-stage MM.

Epidermal Growth Factor Facilitates Melanoma Lymph Node Metastasis by Influencing Tumor Lymphangiogenesis

Alterations in epidermal growth factor (EGF) expression are known to be of prognostic relevance in human melanoma, but EGF-mediated effects on melanoma have not been extensively studied. As lymph node metastasis usually represents the first major step in melanoma progression, we were trying to identify a potential role of primary tumor-derived EGF in the mediation of melanoma lymph node metastases. Stable EGF knockdown (EGFkd) in EGF-high (M24met) and EGF-low (A375) expressing melanoma cells was generated. Only in EGF-high melanoma cells, EGFkd led to a significant reduction of lymph node metastasis and primary tumor lymphangiogenesis in vivo, as well as impairment of tumor cell migration in vitro. Moreover, EGF-induced sprouting of lymphatic but not of blood endothelial cells was abolished using supernatants of M24met EGFkd cells. In addition, M24met EGFkd tumors showed reduced vascular endothelial growth factor-C (VEGF-C) expression levels. Similarly, in human primary melanomas, a direct correlation between EGF/VEGF-C and EGF/Prox-1 expression levels was found. Finally, melanoma patients with lymph node micrometastases undergoing sentinel node biopsy were found to have significantly elevated EGF serum levels as compared with sentinel lymph node-negative patients. Our data indicate that tumor-derived EGF is important in mediating melanoma lymph node metastasis.

Immobilized carboxymethylated dextran coatings for enhanced ELISA

We here report the development of a new generation of enzyme-linked immunosorbent assay (ELISA) that takes advantage of a low-fouling carboxymethylated dextran (CMD) layer chemically grafted on ELISA wells. In our approach, the overnight capture antibody adsorption step found in classical ELISA was replaced by a covalent attachment step to the CMD layer completed in 15min. As a model, the potential of our approach was highlighted using commercially available anti-human epidermal growth factor (EGF) antibodies to quantify EGF present in various samples. Of interest, the grafted CMD layer was found to be as efficient as the commonly used bovine serum albumine (BSA) to reduce non-specific adsorption, thus eliminating the need of a time-consuming BSA blocking step normally required in classical ELISA. Our results demonstrated similar specificity, affinity, and intra- and inter-assay variations regardless of the diluent used in the assay (BSA-based diluent or protein-free buffer solution) when compared to standard ELISA. Finally, accuracy and precision of the CMD-based ELISA were verified by a spike and recovery test. Dilutions of recombinant human EGF in serum from healthy human volunteers showed almost-perfect linearity and mean recovery rates ranging between 90 and 110%.

Prognostic value of circulating cytokines for stage III colon cancer

BackgroundThis study was to determine preoperative serum levels of epidermal growth factor (EGF), interleukin-6 (IL-6), and C-reactive protein (CRP) in stage III colon cancer and correlate them with disease status and prognosis. The circulating EGF in correlation with primary site epidermal growth factor receptor (EGFR) was also evaluated. MethodsSeventy-seven patients with curatively resected stage III colon cancer were selected for analysis. Enzyme-linked immunosorbent assay was used to determine EGF and IL-6 serum levels, and serum CRP levels were measured via immunoturbidimetry. EGFR expression was observed with immunohistochemical studies. ResultsThe median levels of EGFR, IL-6, and CRP were 189.4 pg/mL, 9.09 pg/mL, and 1.4 mg/mL, respectively. The factors related to recurrence with statistical significance included positive node status (P = 0.041), lymphovascular invasion (P = 0.001), and preoperative IL-6 level ≥9 pg/mL (P = 0.020). CRP and EGF levels were not significantly associated with disease-free survival rates (P = 0.438 and P = 0.309, respectively). Multivariate analysis using Cox’s proportion model revealed that lymph node status was the single independent prognostic factor for predicting time until recurrence (odds ratio, 4.99; 95% confidence interval, 1.09–22.91; P = 0.038). ConclusionIL-6 expression in stage III colon cancer patients appears to be a prognostic marker of tumor behavior. No correlations between serum EGF concentrations and tumor EGFR positivity were found in this study.

Serum epidermal growth factor predicts cognitive functions in early, drug-naive Parkinson’s disease patients

Epidermal growth factor (EGF) has been proposed as a candidate biomarker for cognitive impairment in Parkinson's disease (PD). We aimed to assess the relationship between serum EGF and cognitive functions in early, drug-naive PD patients and evaluate the predictive value of EGF on cognitive functions in a 2-year follow-up study. Serum EGF was measured in 65 early, drug-naive PD patients, that underwent a comprehensive neuropsychological battery. Motor symptoms were assessed by means of the Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III). Neuropsychological evaluation was repeated after 2 years. Spearman's rank correlation was used to assess the relationship between serum EGF levels and neuropsychological variables. Linear regression analysis was used to evaluate the relationship between EGF and neuropsychological scores as well as other variables (age, gender, UPDRS-III, levodopa equivalent dose, and type of treatment at follow-up) potentially affecting cognitive performance. Variation over time in cognitive scores was analyzed using repeated-measures ANOVA. At baseline, EGF was the only significant variable associated with performance on semantic fluency (R (2) = 0.131; p = 0.005). EGF levels (p = 0.025), together with UPDRS-III (p = 0.009) and age (p = 0.011), were associated with performance on frontal assessment battery (R (2) = 0.260). At 2-year follow-up, EGF was the only significant variable to predict performance on semantic fluency (R (2) = 0.147; p = 0.025) and color naming task of Stroop color-word test (R (2) = 0.121; p = 0.044). Serum EGF levels are related to frontal and temporal cognitive functions in early, drug-naive PD patients and predict performance on frontal and posterior cognitive functions at 2-year follow-up. EGF is proposed as a potential serum biomarker for early cognitive impairment in PD.

Repeated dose intramuscular injection of the CIMAvax-EGF vaccine in Sprague Dawley rats induces local and systemic toxicity

CIMAvax-EGF consists of a human recombinant epidermal growth factor (EGF), coupled to P64k, a recombinant carrier protein from N. meningitis, and Montanide ISA 51 as adjuvant. The vaccine immunization induces a specific antibody production, inhibiting the EGF/EGF-R interaction through EGF deprivation. The objective of this study was to assess the CIMAvax-EGF toxicity in Sprague Dawley rats after intramuscular administration of repeated doses (6 months) and at the same time to determine if rat is a relevant species for studying CIMAvax-EGF vaccine. Rats were randomly distributed into four groups: control, Montanide ISA 51, treated with 1× and 15× of human total dose of the antigen. Animals were immunized weekly during 9 weeks, plus 9 immunizations every 14 days. Rats were inspected daily for clinical signs. Body weight, food consumption, and rectal temperature were measured during the administration of doses. Blood samples were collected for hematological, serum biochemical determinations and EGF titles at the beginning, three months and at the end of experimentation. Gross necropsy and histological examination of tissues were performed on animals at the end of the assay. Vaccine provoked the apparition of antibodies against EGF in the rats, demonstrating rat species relevance in these studies. Body weight gain, food and water consumption were not affected. CIMAvax-EGF and Montanide ISA 51 produced local damage at the administration site, showing multiple cysts and granulomas. Both vaccine-treated groups showed neutrophil elevation, besides an AST increase probably related to the damage at the administration site. Rectal temperature was found to be significantly higher in 15× treated group after immunizations, probably induced by the inflammatory process at the injection site. In summary, the clinical pathology findings together with the body temperature results, appear to be caused by the inflammatory reaction at the administration site of the vaccine, mainly mediated by the oil-based adjuvant Montanide ISA 51, probably enhanced by the immunological properties of the antigen. This study showed evidences that intramuscular administration during 26 weeks of CIMAvax-EGF at doses up to 15× human total dose is well tolerated in rats and it has a clinical importance since this long lasting study in relevant species allows to treat cancer patients with tumors during long periods with relative weight safety margin.

Healthy ageing through regulated proteostasis

During metazoan life, protein homeostasis (proteostasis) declines with age due to impaired proteasome activity. The signalling pathways activated by growth factors that regulate proteostasis and their importance to ageing are just emerging. In this issue, Liu et al report a crucial role of epidermal growth factor (EGF) in regulating Caenorhabditis elegans lifespan through the RAF/MAPK pathway. EGF signalling activates the ubiquitin–proteosome system (UPS) and represses the chaperone machinery by modulating the expression of several ageing‐related genes (gerontogenes). This strategic switch in controlling global protein turnover provides novel insights into the molecular mechanisms driving ageing in multi‐cellular organisms.

Clinical significance of serum hepatocyte growth factor and epidermal growth factor gene somatic mutations in patients with non-squamous non-small cell lung cancer receiving gefitinib or erlotinib

A study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and serum hepatocyte growth factor (HGF) for their associations with response to gefitinib therapy and prognostic impact. An enzyme-linked immunosorbent assay was used to determine levels of HGF in serum from 96 Japanese patients with advanced non-squamous NSCLC. The peptic nucleic acid-locked nucleic acid clamp method was used to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and risk factors associated with prognosis. HGF-positive serum status (hazard ratio, 1.536; 95% confidence interval, 1.042-2.400; P = 0.0295) had a significant and independent negative effect on progression-free survival among patients with wild-type EGFR. We demonstrate that having HGF-positive serum is predictive of a negative response to gefitinib therapy in patients with advanced NSCLC who harbor wild-type EGFR.