Plasma Epidermal Growth Factor Levels Research Articles

Alteration of inflammatory factors between chronic stroke and post‐stroke dementia: A cross‐sectional study

AbstractBackgroundInflammation may play a role in the pathological processes of stroke and post‐stroke dementia. However, there has not been compared and discussed upon the alterations among the plasma inflammatory factors from stroke to post‐stroke dementia.MethodIn this study, an age‐ and gender‐matched normal controls and ischemic stroke patients with (PSD) or without (PSNoD) dementia had been recruited. The ischemic stroke patients had further examined the 30‐day Modified Rankin scale (MRS), stroke infarction subtypes, anti‐cholinergic treatment status and Clinical Dementia Rating (CDR). Levels of plasma inflammatory factors epidermal growth factor (EGF), growth‐regulated oncogene (GRO), soluble CD40 ligand (sCD40L), Interleukin 7 (IL‐7) and Interleukin 4 (IL‐4) were measured by Milliplex map human cytokine/chemokine magnetic bead panel assay. The butylcholinesterase (BChE) activity and plasma D‐amino acid oxidase (DAO) were also included in these analyses due to our previous published report [1, 2].ResultThe ischemic stroke patients showed significantly higher percentage of hypertension (HTN), Diabetes mellitus (DM) and self‐report smoking than normal controls (p<0.01). Normal controls had significant higher plasma EGF, GRO, sCD40L, IL‐7, but lower plasma DAO levels than the ischemic stroke patients (p<0.003). In comparisons between the PSD and PSNoD patients, the PSD showed significantly higher 30‐day MRS, CDR, percentage of anti‐cholinergic treatment than the PSNoD (p<0.014) after adjust with age. The plasma BChE activity showed lower levels in PSD than PSNoD (p=0.0002) after adjust with age.ConclusionThe inflammatory factors of EGF, GRO, sCD40L, IL‐7 and plasma DAO levels were mainly associated with ischemic stroke. The BChE activity may be a better indicator for the post‐stroke dementia.

Decreased plasma epidermal growth factor (EGF) levels in patients with severe chronic obstructive pulmonary disease

Abstract Background Chronic mucus hypersecretion is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with epidermal growth factor (EGF) activity. Aberrant EGF and its receptor signalling can cause airway hyperproliferation, increase in mucous cell differentiation and mucus hyperproduction. Furthermore, it can also promote subepithelial fibrosis and excessive collagen deposition in COPD. The objective of this research was to investigate the plasma levels of EGF in smokers with COPD in comparison with clinically healthy smokers. In addition, the relationship between the plasma levels of EGF and clinical features was investigated. Methods A cross-sectional study included 82 clinically stable male patients with mild-to-very severe COPD (mean age: 64.5±8.6 years), and the control group consisted of 86 healthy male smokers (mean age: 61.6±9.5 years). To define COPD, we performed spirometry and classified COPD using Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. We analyzed the levels of EGF by enzyme-linked immunosorbent assay in plasma. Results The mean serum levels of EGF were significantly lower in smokers with COPD than those in controls (69.30 and 83.82 pg/mL, respectively, p = 0.046). The plasma levels of EGF were significantly different (p = 0.004) between mild COPD and moderate-to-very severe COPD. There were no significant differences between the levels of EGF in plasma of spontaneous sputum producers (COPD patients) vs. nonsputum producers (p = 0.101) and between nonexacerbated COPD and exacerbated COPD patients(p = 0.138). Conclusions There is a significant difference in the plasma levels of EGF in male smokers with COPD as compared with male healthy smokers. Our findings suggest that the plasma levels of EGF may contribute to the pathogenesis of COPD.

Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice.

Cerebrovascular (CV) dysfunction is emerging as a critical component of Alzheimer’s disease (AD), including altered CV coverage. Angiogenic growth factors (AGFs) are key for controlling CV coverage, especially during disease pathology. Therefore, evaluating the effects of AGFs in vivo can provide important information on the role of CV coverage in AD. We recently demonstrated that epidermal growth factor (EGF) prevents amyloid-beta (Aβ)-induced damage to brain endothelial cells in vitro. Here, our goal was to assess the protective effects of EGF on cognition, CV coverage and Aβ levels using an AD-Tg model that incorporates CV relevant AD risk factors. APOE4 is the greatest genetic risk factor for sporadic AD especially in women and is associated with CV dysfunction. EFAD mice express human APOE3 (E3FAD) or APOE4 (E4FAD), overproduce human Aβ42 and are a well characterized model of APOE pathology. Thus, initially the role of APOE and sex in cognitive and CV dysfunction was assessed in EFAD mice in order to identify a group for EGF treatment. At 8 months E4FAD female mice were cognitively impaired, had low CV coverage, high microbleeds and low plasma EGF levels. Therefore, E4FAD female mice were selected for an EGF prevention paradigm (300 μg/kg/wk, 6 to 8.5 months). EGF prevented cognitive decline and was associated with lower microbleeds and higher CV coverage, but not changes in Aβ levels. Collectively, these data suggest that EGF can prevent Aβ-induced damage to the CV. Developing therapeutic strategies based on AGFs may be particularly efficacious for APOE4-induced AD risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0387-3) contains supplementary material, which is available to authorized users.

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin‐binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment‐by‐marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild‐type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild‐type (WT) patients (chemo HR = 0.98, 95% CI = 0.74–1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05–2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02–2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67–1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68–13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31–2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88–1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32–1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab.

Assessment of a multi-assay biological diagnostic test for mood disorders in a Japanese population

The current diagnostic tests for mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), have limitations. Inflammatory markers, growth factors, and oxidative stress markers are involved in the pathophysiology of mood disorders. A multi-assay biological diagnostic test combining these biomarkers might improve diagnostic efficiency. The plasma levels of soluble tumor necrosis factor receptor 2 (sTNFR2), epidermal growth factor (EGF), and myeloperoxidase were measured in 40 MDD patients, 40 BD patients and 40 controls in a Japanese population. We also investigated the plasma levels of these markers in 40 patients with schizophrenia to determine the utility of these markers in differential diagnosis. The plasma levels of sTNFR2 were significantly higher in BD and schizophrenia patients than in controls. The plasma levels of EGF and myeloperoxidase were significantly higher in patients with BD than in controls. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and mood disorders was 69.2%, with a sensitivity and specificity of 62.5% and 82.5%, respectively. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and BD was 85.0%, with a sensitivity and specificity of 77.6% and 92.5%, respectively. Our results suggest that sTNFR2 and EGF could be biological markers of BD. Further studies are needed to determine the utility of these markers in diagnostic tests for mood disorders.

Plasma epidermal growth factor decreased in the early stage of Parkinson's disease.

Epidermal growth factor (EGF) is a neurotrophic factor that plays an important role in Parkinson's disease (PD). We measured plasma EGF level in PD, essential tremor (ET) and normal controls to investigate whether it changes in PD and whether it is associated with motor and non-motor symptoms of PD. 100 patients with PD, 40 patients with ET as disease control and 76 healthy persons were enrolled in the present study. Motor and non-motor symptoms were assessed by different scales. Plasma EGF levels of three groups were measured by enzyme-linked immunosorbent assay kit. Spearman test and linear logistics regression model were used to test the correlation of EGF with motor and non-motor symptoms of PD. Plasma EGF level was significantly decreased in early PD patients compared with normal control, but not in advanced PD patients. Interestingly, plasma EGF level was significantly increased in advanced PD and total PD patients compared with ET patients, but not in early PD patients. In addition, plasma EGF level was correlated with UPDRS-III scores in PD. Also plasma EGF level was correlated with UPDRS-III scores and NMS scores in early PD. Our results suggested that plasma EGF decreased in the early stage of PD and increased later on in the PD disease course. Also, plasma EGF level was increased significantly in PD compared with ET patients and correlated with motor and non-motor symptoms in early PD.

Reduced expression of the epidermal growth factor signaling system in preeclampsia

IntroductionThe epidermal growth factor (EGF) signaling system regulates trophoblast differentiation, and its disruption could contribute to perinatal disease. We hypothesized that this pathway is altered in preeclampsia, a disorder associated with trophoblast apoptosis and failure to invade and remodel the uterine spiral arteries. MethodsSix EGF family peptides and a truncated EGF receptor splice variant (p110/EGFR) were examined using immunohistochemistry in the trophoblast of placentas (N = 76) from women with preeclampsia, and compared to placentas from women of similar gestational age (GA) with preterm labor (PTL) or small for gestational age (SGA) fetuses, as well as normal term placentas. EGF, transforming growth factor-α (TGFA), and heparin-binding EGF-like growth factor (HBEGF) were evaluated using ELISA in maternal plasma from another 20 pregnancies with or without preeclampsia. Cell death was evaluated in the HTR-8/SVneo human cytotrophoblast cell line using TUNEL to evaluate the protective effects of EGF peptides. ResultsTrophoblast HBEGF, TGFA, and EGF were significantly reduced in preeclampsia compared to PTL and SGA, while p110/EGFR accumulated significantly on the surface of the chorionic villi (p < 0.05). Plasma EGF levels were significantly decreased in preeclamptic patients, compared to non-preeclamptic patients (p < 0.05). HBEGF, EGF, TGFA, epiregulin, and betacellulin each blocked cytotrophoblast cell death in vitro (p < 0.05). DiscussionThree members of the EGF family are dysregulated in placentas with preeclampsia, whereas p110/EGFR, a potential EGF receptor antagonist, is overexpressed. These findings are consistent with the concept that disruption of the EGF signaling system contributes to aberrant trophoblast development associated with preeclampsia.

Expression of epidermal growth factor, transforming growth factor-β1 and adiponectin in nipple aspirate fluid and plasma of pre and post-menopausal women.

BackgroundNipple aspirate fluid (NAF) contains large amounts of protein thought to reflect the microenvironment of the breast, and is of interest in breast cancer prevention research. The correlation between specific NAF proteins to plasma concentrations have not been well studied in healthy women. We collected matched NAF and plasma from 43 healthy pre and postmenopausal women participating in an early phase clinical study to compare the levels of putative cancer protein biomarkers. We compared baseline NAF and plasma levels of epidermal growth factor (EGF), transforming growth factor-beta 1 (TGF-β1), and adiponectin and evaluated menopausal status and body mass index (BMI) as potential modifying factors.FindingsNAF and plasma levels of EGF, TGF-β1 and adiponectin were not correlated. EGF and TGF-β1 levels in NAF of premenopausal women were significantly higher than postmenopausal women (P’s < 0.01). These differences by menopausal status were not observed in plasma. Both NAF and plasma adiponectin levels were non-significantly higher in postmenopausal women. NAF biomarker levels were not associated with BMI whereas plasma EGF, TGF-β1 and adiponectin levels in postmenopausal women were all inversely correlated with BMI (P’s < 0.05).ConclusionsProtein biomarkers differ significantly between NAF and plasma and are affected differently by both BMI and menopausal status. This study demonstrates important differences in biological information gained by characterizing biomarkers in NAF compared to plasma and suggests each sample source may independently inform on breast cancer risk.

Decreased Epidermal Growth Factor (EGF) Associated with HMGB1 and Increased Hyperactivity in Children with Autism

BackgroundAutism spectrum disorders (ASDs), characterized by impaired social interactions and deficits in verbal and nonverbal communication, are thought to affect 1 in 88 children in the United States. There is much support for the role of growth factors in the etiology of autism. Recent research has shown that epithelial growth factor (EGF) is decreased in young autistic children (2–4 years of age). This study was designed to determine plasma levels of EGF in an older group of autistic children (mean age 10.6 years) and to correlate these EGF levels with putative biomarkers HGF, uPA, uPAR, GAD2, MPO GABA, and HMGB1, as well as symptom severity of 19 different symptoms.Subjects and methodsPlasma from 38 autistic children, 11 children with pervasive developmental disorder (PDD-NOS) and 40 neurotypical, age and gender similar controls was assessed for EGF concentration using ELISAs. Severity of 19 symptoms (awareness, expressive language, receptive language, (conversational) pragmatic language, focus/attention, hyperactivity, impulsivity, perseveration, fine motor skills, gross motor skills, hypotonia (low muscle tone), tiptoeing, rocking/pacing, stimming, obsessions/fixations, eye contact, sound sensitivity, light sensitivity, and tactile sensitivity) was assessed and then compared to EGF concentrations.ResultsIn this study, we found EGF levels in autistic children and those with PDD-NOS to be significantly lower when compared with neurotypical controls. EGF levels correlated with HMGB1 levels but not the other tested putative biomarkers, and EGF correlated negatively with hyperactivity, gross motor skills, and tiptoeing but not other symptoms.ConclusionsThese results suggest an association between decreased plasma EGF levels and selected symptom severity. We also found a strong correlation between plasma EGF and HMGB1, suggesting inflammation is associated with decreased EGF.

A study of the functional significance of epidermal growth factor in major depressive disorder

The precise mechanism of major depressive disorder (MDD) is poorly understood. On the basis of the neurotrophin hypothesis, initial findings from our previous studies, and the functions of epidermal growth factor (EGF) in the central nervous system, we proposed that EGF might contribute to the development of MDD, which was investigated in this study. Eight single nucleotide polymorphisms (SNPs) within the EGF gene were genotyped in 463 patients with MDD and 413 control participants among a Chinese population; of these, the plasma EGF levels of 210 patients and 223 controls were determined using the enzyme-linked immunosorbent assay. To determine the effect of functional SNPs on EGF secretion in HEK293 cells, EGF levels in the supernatants of cultured cells were also assessed. None of the informative SNPs showed an allelic association with MDD, but the cis-phase interaction between rs11569017 and rs11569126 was strongly associated with the illness (P=0.0027). The EGF levels in plasma were significantly lower in the patient group than in the control group (P<0.0001). The EGF levels were also significantly lower in patients with the rs11569017-TT genotype than those with either the AA genotype (P=0.013) or the AT genotype (P=0.004); the rs11569017 minor allele significantly affected the expression of the EGF gene (P=0.0004). The cis-phase interaction between the SNPs within the EGF locus may contribute toward the etiology of MDD. The plasma EGF levels may be a useful biomarker for the early diagnosis, treatment, and prognosis of major psychiatric disorders.

Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease

Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD. A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8-fold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.

T14.4 Concurrent eclampsia and HELLP syndrome is a catastrophic event

The epidermal growth factor (EGF) signaling system regulates trophoblast differentiation, and its disruption could contribute to perinatal disease. We hypothesized that this pathway is altered in preeclampsia, a disorder associated with trophoblast apoptosis and failure to invade and remodel the uterine spiral arteries.Six EGF family peptides and a truncated EGF receptor splice variant (p110/EGFR) were examined using immunohistochemistry in the trophoblast of placentas (N = 76) from women with preeclampsia, and compared to placentas from women of similar gestational age (GA) with preterm labor (PTL) or small for gestational age (SGA) fetuses, as well as normal term placentas. EGF, transforming growth factor-α (TGFA), and heparin-binding EGF-like growth factor (HBEGF) were evaluated using ELISA in maternal plasma from another 20 pregnancies with or without preeclampsia. Cell death was evaluated in the HTR-8/SVneo human cytotrophoblast cell line using TUNEL to evaluate the protective effects of EGF peptides.Trophoblast HBEGF, TGFA, and EGF were significantly reduced in preeclampsia compared to PTL and SGA, while p110/EGFR accumulated significantly on the surface of the chorionic villi (p < 0.05). Plasma EGF levels were significantly decreased in preeclamptic patients, compared to non-preeclamptic patients (p < 0.05). HBEGF, EGF, TGFA, epiregulin, and betacellulin each blocked cytotrophoblast cell death in vitro (p < 0.05).Three members of the EGF family are dysregulated in placentas with preeclampsia, whereas p110/EGFR, a potential EGF receptor antagonist, is overexpressed. These findings are consistent with the concept that disruption of the EGF signaling system contributes to aberrant trophoblast development associated with preeclampsia.

Minimally invasive colorectal resection is associated with a rapid and sustained decrease in plasma levels of epidermal growth factor (EGF) in the colon cancer setting

Epidermal growth factor (EGF) stimulates tumor growth directly via tumor cell EGF receptors or indirectly via its proangiogenic effects. This study's purpose was to determine the impact of minimally invasive colorectal resection (MICR) on postoperative (postop) plasma EGF levels in the colorectal cancer (CRC) and benign disease settings and to see if preoperative (PreOp) EGF levels are altered in cancer patients. MICR patients with benign pathology (n = 40) and CRC (n = 48) had blood samples taken PreOp and on postoperative days (POD) 1 and 3. In some patients, late samples were taken between POD7 and POD60; these were bundled into 7-day blocks and considered as single time points. EGF levels were determined by enzyme-linked immunosorbent assay (ELISA) and results were reported as mean ± SD after logarithmic transformation. The Student t test was used (p < 0.008 after Bonferroni correction). The cancer and benign groups were comparable except for age. The mean PreOp CRC plasma EGF level (122.9 ± 75.9 pg/ml) was significantly higher than that of the benign group (85.3 ± 38.5 pg/ml) (p = 0.015). The cancer group's EGF levels were significantly decreased on POD1 and POD3 and for the POD31-55 time point (mean EGF level = 63.1 ± 42.2 (n = 10). The benign group's POD3 and POD7-14 EGF levels were significantly lower than the PreOp level; later levels returned toward baseline. Small late sample size limited analysis. Plasma EGF levels are significantly higher in cancer patients. MICR is associated with a significant decrease in EGF levels early postop in both cancer and benign settings. Unlike the benign group, EGF blood levels in cancer patients remain low during the second postop month. A larger study with more late samples is needed to verify these results. EGF may have value as a tumor marker.

EGF promoter SNPs, plasma EGF levels and risk of breast cancer in Chinese women

Epidermal growth factor (EGF), a potent mitogenic peptide, plays an important role in the development of cancers, including breast cancer. Previous studies showed that plasma EGF levels may influence the risk of cancer. In the current study, we hypothesized that genetic variants in the promoter region of EGF may influence plasma EGF levels and therefore are associated with breast cancer susceptibility. We genotyped three EGF polymorphisms (G61A, G-1380A, and A-1744G) in the promoter region by PCR-RFLP and measured plasma EGF levels using an enzyme immunoassay in a case-control study of Chinese women. We found that the mean plasma EGF levels in breast cancer patients (249.06 +/- 197.54 pg/ml) were significantly lower than those in controls (982.41 +/- 375.57 pg/ml, P < 0.001). There was a significant difference of plasma EGF levels among different genotypes carriers of the G-1380A locus in 654 controls (P = 0.007). After adjustment for age, body mass index, family history of cancer, age at menarche, and menopause status, EGF-1380AA carriers had significantly higher plasma EGF levels than -1380GG carriers did (P = 0.003). However, we did not find any significant associations between the three EGF polymorphisms (G61A, G-1380A, and A-1744G) and the risk of breast cancer. These findings indicated that plasma EGF levels served as a protective marker against breast cancer in our study and EGF G-1380A variant might be a modifier on it. Further studies are warranted to verify these findings.

Biochip Array‐based Analysis of Plasma Cytokines in HIV Patients with Immunological and Virological Discordance

Assessment of cytokines in body fluids or cells provides important information in understanding the disease process and designing treatment strategies. Recent introduction of antibody-based protein arrays have provided investigators simultaneous and specific detection of multiple analytes in a single sample using minimum volumes. In this study, we used a biochip array system capable of measuring 12 cytokines and growth factors (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1alpha, IL-1beta, IFN-gamma, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF)) in HIV patients with immunological and virological discordance (discordant) to find out differences if any, in their plasma cytokine profiles when compared with concordant HIV-infected individuals. A sandwich chemiluminescent assay was performed with plasma specimens of 110 HIV patients (55 discordant, 55 concordant) and 22 normal healthy individuals followed by enzyme-linked immunosorbent assay (ELISA) to the confirm levels of cytokines and growth factors that showed significant differences in the two groups. The discordant HIV patients showed significantly higher levels of plasma VEGF (P = 0.001) and EGF (P = 0.034) levels when compared with concordant patients. Overall, the patients showed significantly higher levels of TNF-alpha, MCP-1 and VEGF when compared with the normal healthy controls (P < 0.05). ELISA for VEGF (P < 0.001) and EGF (P = 0.004) confirmed the comparison obtained with biochip array, between the discordant and concordant patients. The results of cytokine quantitation by biochip array and ELISA confirmed that this technology is not only comparable but also has a good potential in the future applications involving measurement of multiple cytokines with limiting specimens.

Local Reduction of Organ Size in Transgenic Mice Expressing a Soluble Insulin-Like Growth Factor II/Mannose-6-Phosphate Receptor

Genetic evidence suggests that the insulin-like growth factor II (IGF-II)/mannose-6-phosphate receptor (IGF2R) slows growth. A soluble form of IGF2R (sIGF2R) is produced by proteolytic cleavage of the intact cellular receptor and is found at high levels in fetal and neonatal plasma. To test the hypothesis that sIGF2R modulates organ size in vivo, we generated transgenic mice expressing a mouse Igf2r complementary DNA in which the transmembrane domain sequence was deleted. The transgene was driven by the keratin-10 promoter and was expressed at the highest levels in the skin and alimentary canal. Transgenics showed disproportionately reduced size of the alimentary canal, where the wet weight was decreased by 9–20% and the dry weight was decreased by 20–30%, whereas the water content per unit dry weight was not significantly changed. In addition, the circulating levels of IGF-II and the latent form of transforming growth factor-β1 were increased by 58–77% and 56–140%, respectively, whereas plasma epidermal growth factor levels showed a 24–35% reduction. The serum and tissue activities of four lysosomal enzymes were not affected, with the exception of the colon in the line expressing the transgene at highest levels, where enzyme activities were decreased compared with control values. These results support a significant role for the sIGF2R in local modulation of organ size in vivo.

Local reduction of organ size in transgenic mice expressing a soluble insulin-like growth factor II/mannose-6-phosphate receptor.

Genetic evidence suggests that the insulin-like growth factor II (IGF-II)/mannose-6-phosphate receptor (IGF2R) slows growth. A soluble form of IGF2R (sIGF2R) is produced by proteolytic cleavage of the intact cellular receptor and is found at high levels in fetal and neonatal plasma. To test the hypothesis that sIGF2R modulates organ size in vivo, we generated transgenic mice expressing a mouse Igf2r complementary DNA in which the transmembrane domain sequence was deleted. The transgene was driven by the keratin-10 promoter and was expressed at the highest levels in the skin and alimentary canal. Transgenics showed disproportionately reduced size of the alimentary canal, where the wet weight was decreased by 9-20% and the dry weight was decreased by 20-30%, whereas the water content per unit dry weight was not significantly changed. In addition, the circulating levels of IGF-II and the latent form of transforming growth factor-beta1 were increased by 58-77% and 56-140%, respectively, whereas plasma epidermal growth factor levels showed a 24-35% reduction. The serum and tissue activities of four lysosomal enzymes were not affected, with the exception of the colon in the line expressing the transgene at highest levels, where enzyme activities were decreased compared with control values. These results support a significant role for the sIGF2R in local modulation of organ size in vivo.

Platelet epidermal growth factor in thyroid disorders.

We evaluated the concentration of epidermal growth factor (EGF) in platelets, serum and plasma obtained from 47 patients with Graves' disease, 7 with hypothyroidism and 20 healthy subjects. The platelets of the subjects were collected from platelet rich plasma and lysed by freezing and thawing. Subsequently the platelet debris was treated with Triton X-100. The EGF concentration was determined by homologous radioimmunoassay. The concentration of EGF in the platelets in 14 patients with untreated Graves' disease was significantly higher than that in the healthy controls. After treating these 14 patients with antithyroid agents, the EGF concentration in the platelets decreased to the level of the healthy controls. The EGF concentration in the platelets in the 7 untreated hypothyroid patients decreased after replacement therapy with thyroxine. The mean volume of the platelets in the 14 patients with untreated Graves' disease was significantly larger than in the control and decreased after treatment with antithyroid agents. The serum and plasma levels of EGF in the 7 untreated hypothyroid increased after replacement therapy. In conclusion, thyroid function affected the concentration of EGF in the platelets of patients with thyroid disorders.

Humoral growth factors in plasma and liver tissue during liver regeneration and malnutrition

Objective: To investigate the potential of a series of growth factors which may be involved in liver regeneration. Design: The concentrations of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and insulin-like growth factor I (IGF-I) were measured in plasma and liver tissue 48h after liver resection or sham operation combined with malnutrition. Methods: Forty-four rats were randomized to either semistarvation or ordinary food intake; half of each group was partially hepatectomized, and the other half underwent a sham operation and served as controls. Growth factors were measured by radioimmunoassay. Results: Plasma EGF levels were increased following semistarvation and were also increased in plasma and liver tissue after 48 h of liver regeneration. Tumour necrosis factor-alpha levels did not change following either malnutrition or liver regeneration. Insulin-like growth factor I levels were raised in liver tissue after 48 h of regeneration. Conclusion: These results suggest that EGF has a central role in liver regeneration; the role of IGF-I is uncertain, while TGF-alpha does not seem to be involved in regeneration at 48 h.

A physiological role of epidermal growth factor in cell kinetics of gastric epithelium

Administration of epidermal growth factor (EGF) stimulates DNA synthesis in gut epithelial cells and inhibits gastric acid secretion. A physiological role of EGF in cell kinetics of gastric epithelium, however, has not been fully understood. In mature male mice, large amounts of EGF are produced in the submandibular glands, and sialoadenectomy (removal of the submandibular glands) causes a marked reduction of plasma EGF levels. For the evaluation of a biophysical functioon of EGF, sialoadenectomized mice and sham-operated mice were injected with 3H-thymidine to compare the proliferative activity and the cell-turnover of gastric epithelium between the two groups using the autoradiographic analysis. When mice were killed 90 min after a single injection of 3H-thymidine, the percentages of fundic gland mucosal cells radiolabeled in sialoadenectomized and sham-operated mice were 27.3 ± 5.0 % and 26.3 ± 5.8 % (mean ±SD), respectively. The difference was not significant (p>0.05). Similarly, the labeling indices of pyloric gland mucosal cells were not different between the two groups (26.7 ± 4.3% vs 27.8 ± 3.7%, p>0.05). In contrast, when mice were given 17 repeated injections of 3H-thymidine at 6 hr intervals and killed 48 hr after the last injection, labeling indices in sialoadenectomized mice were significantly lower than those in sham-operated mice (35.3 ± 4.3% vs 52.8 ± 1.1% in the fundic gland area; 41.0 ± 6.2% vs 55.1 ± 5.9% in the pyloric gland area, p<0.001, respectively). Treatment of sialoadenectomized mice with EGF (5 mg/mouse per day) completely restored the percentages of the radiolabeled cells to control levels. These findings suggest that endogenous EGF plays a major role in maintaining biological cell-turnover of the mouse gastric epithelium.