Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A>> G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In particular, while both the patients exhibited a severe short stature, GH/IGFI axis functional evaluation revealed a different pathogenetic alteration, suggesting in one patient an upstream alteration (typical GHD) and in the other one a peripheral GH insensitivity.

The lung (in particular the bronchial epithelium) is a major site for tumor formation in humans. Environmental factors in conjunction with genetic factors are important determinants in this disease. The acquisition of defects in the control of proliferation and differentiation appears to constitute crucial steps in the transition of a normal to a neoplastic cell. Several factors have been identified that control positively or negatively the proliferation and differentiation of tracheobronchial epithelial cells. These factors include EGF/TGF alpha, TGF beta, insulin/IGFI, KGF, certain cytokines, retinoids, and activators of protein kinase C. Studies with neoplastic cells have identified several protooncogenes and tumor suppressor genes whose gene products are involved in the regulation of cell growth of normal tracheobronchial epithelial cells, and when mutated, lost, or activated, bring about a neoplastic phenotype. Future studies on the precise function of these genes will help to elucidate the mechanisms by which proliferation and differentiation in normal tracheobronchial epithelial cells are regulated and help to understand the molecular changes involved in diseases such as cancer.

IGF-I gene transcription is regulated by two promoters--the major promoter which is active in all tissues and regulates transcription of IGF-I mRNAs that contain exon 1 and a second promoter which regulates transcription of IGF-I mRNAs that contain exon 2 and from which significant transcription is restricted to the liver. The major promoter is a TATAA-less promoter that lacks both a CAAT box and SP1 binding sites and that utilizes multiple transcription initiation sites. The current studies were designed to delineate the functional elements of the major promoter. Transient transfection assays using rat C6 glioma cells and rat dermal fibroblasts in primary culture demonstrated that basal activity of the major promoter was located between -18 (with +1 defined as the most 5' transcription initiation site in exon 1) and +78 of exon 1. DNase I footprinting, which was performed using nuclear extracts from rat C6 glioma cells, demonstrated protein binding to a sequence that extended from -10 to +9 (termed IGFI-FP1). In gel shift assays, binding of C6 cell nuclear proteins to a 34-basepair (bp) oligonucleotide that contained IGFI-FP1 resulted in the formation of three specific protein-DNA complexes. The functional role of protein binding to IGFI-FP1 was examined by mutating the sequences between either -4 and -2 or -9 and -7 in IGF-I-luciferase fusion genes that contained either 412 or 18 bp of 5'-flanking region and 302 bp of exon 1. Both of these mutations altered protein binding to IGFI-FP1 as demonstrated by gel shift analysis. Transfection of the wild-type and mutant fusion genes into C6 glioma cells demonstrated that mutation of the nucleotides between -4 and -2 decreased luciferase activity to approximately 50% of wild-type activity, whereas mutation of the nucleotides between -9 and -7 decreased luciferase activity to 11-35% of wild-type activity. These data demonstrate that: (i) basal activity of the major promoter of the rat IGF-I gene is localized to the region between -18 and +78 of exon 1; (ii) protein binding sites are present within this region of the major promoter; and (iii) protein binding to this region contributes to basal expression of the IGF-I gene.

The aim of this study was to assess the GH-IGFI axis, GH receptor availability, as reflected by the levels of GH-BP, and the amount of GH-dependent IGFBP-3 in adult IDDM patients with different degrees of metabolic control. Thus, 10 adult well-controlled IDDMs (HbA1 7.8 +/- 0.4%), 10 adult non-ketotic poorly controlled IDDMs (HbA1 13.3 +/- 7%) and 14 sex- and age-matched healthy controls were subjected to two intravenous GH-RH stimulation tests with 0.1 and 1.0 microg/kg body weight respectively, and a plasma IGF-1 generation test induced by the administration of hGH. Poorly controlled IDDM patients exhibited an exaggerated GH response to 1.0 microg/kg of GH-RH when compared to healthy control subjects. Low fasting plasma IGF-1 levels and a blunted IGF-1 response to exogenously administered hGH were also found in poorly controlled IDDMs when compared to the healthy control group. GH-BP levels were significantly lower in IDDMs than in normal controls, and correlated positively with the IGF-1 generation capacity after hGH. Serum IGFBP-3 levels measured by RIA were similar in IDDM and control groups. Good glycemic control for 5.7 +/- 0.9 months did not correct the above mentioned abnormalities of the GH-IGF-1 axis. Our findings suggest that IDDM is associated with a diminished availability of GH receptors and synthesis of IGF-1. GH might then increase as a compensatory mechanism, further down-regulating liver GH receptors, and thus perpetuating the initial abnormality.

BACKGROUND

The aim of this study was to assess the accuracy of actual resected liver volume (ARLV) in anatomical liver resections (ALRs) guided by 3-dimensional parenchymal staining using fusion indocyanine green fluorescence imaging (IGFI).

METHODS

Patients eligible for hepatic resection were enrolled in the current study from January 2016 to November 2017. All patients underwent surgery planning based on Medical Image Three-Dimensional Visualization System (MI-3DVS) before the operation, in which predicted resected liver volumes (PRLVs) were calculated. Under 3-dimensional guidance by fusion IGFI, ALRs were performed and ARLVs were measured. Simple linear regression, intra-class correlation coefficient (ICC) and Bland-Altman analysis were used to evaluate the relationship and agreement between PRLV and ARLV.

RESULTS

Of the 27 patients who achieved valid demarcation by fusion IGFI, 12 (44.4%) received hemihepatectomy, while 10 (37.0%) and five (18.5%) underwent sectionectomy and segmentectomy, respectively. The relationship and agreement between PRLV (481.37 ± 189.47 cm³) and ARLV (450.57 ± 205.19 cm³) were then evaluated. The simple regression equation obtained was PRLV = 0.874 × ARLV + 87.75 (R = 0.946; P = 0.000). Meanwhile, ARLV (ICC = 0.943) achieved an excellent agreement with PRLV ( P < 0.001); 25 of 27 dots were in the range of 95% confidence interval in Bland-Altman analysis.

CONCLUSIONS

In the study, these findings validated the consistency between PRLV calculated by MI-3DVS and ARLV guided by fusion IGFI, which proved that IGFI can accurately guide anatomical hepatectomy. Generally, fusion IGFI can provide a valid, feasible and accurate demarcation line, which can confer precision to hepatic resection.

As far as we know, there is no available information about ontogenic changes of tissue concentrations of IGF-I and II and IGFBPs in large mammals. Serum, liver and kidney levels of IGFs and IGFBPs were examined in fetuses at 90 and 110 days of gestation and in pigs at 1d, 3 wk, 3 mo and 6 mo of age. Ontogeny of mRNA levels of IGFs, IGF type I and type II receptors (IGFI-R and IGFII-R), IGFBP-1 and -3 (IGFBPs) and growth hormone receptor (GHR) were also examined by Northern blot analysis in liver, kidney and skeletal muscle of pig. Serum IGF-I, IGF-II and IGFBP-3 concentrations were low during the fetal life and increased after birth. The highest level of IGF-II mRNA was found in fetuses for all studied tissues. In the liver, IGF-I mRNA level and its protein content peaked at 3 wk of age. The highest IGF-II concentration was found at 1d and 3 wk of age. The IGFII-R mRNA remained at a constant level during the whole development period. The most abundant IGFBP-1 mRNA and its protein content were found at birth. The level of IGFBP-2 was high during fetal and early postnatal life. The IGFBP-3 content was relatively low in fetuses and reached the highest level after 3 wk of age. In the kidney, IGFs, IGFBP-3, IGFI-R and IGFII-R as well as GHR mRNA levels were relatively high during the fetal and early postnatal life. The IGFs concentrations were the highest in newborns. In the skeletal muscle, IGFs, IGFBP-3 and IGFI-R mRNA levels decreased with advancing age. During the postnatal life, the high IGFs concentrations in the liver and the kidney correspond to fast growth periods of these organs.

The extracellular matrix-associated glycoprotein secreted protein acidic and rich in cysteine (SPARC) has been implicated in the control of cell proliferation during tissue remodeling, wound healing, and malignant development. Here, we describe a novel mechanism through which SPARC influences cell cycle progression in embryonic fibroblasts derived from Sparc-nullizygous (-/-) mice. SPARC-deficient cells were indistinguishable from wild-type cells in their ability to initiate DNA synthesis after treatment with either fetal bovine serum or platelet-derived growth factor. In contrast, Sparc -/- cells responded poorly to activation of the insulin-like growth factor receptor (IGFI-R) by insulin. This defect was traced to reduced expression of the IGFI-R in Sparc -/- cells. Consistent with impaired cell cycle progression through S-phase, insulin-stimulated Sparc -/- cells also revealed reduced expression of two key regulators of S phase progression (cyclin A and thymidine kinase), whereas expression of the G1 phase progression regulators cmyc or cyclin D1 was unaffected. An examination of the status of retinoblastoma family pocket proteins in Sparc -/- cells revealed a selective and dramatic reduction in levels of the retinoblastoma-related protein p107. Exogenous platelet-derived growth factor restored expression of the IGFI-R and IGFI-R dependent DNA synthesis as well as induction of cyclin A, thymidine kinase, and p107 in insulin-stimulated Sparc -/- cells. These results suggest that SPARC-dependent matrix to cell interactions contribute to the regulation of p107 and cyclin A through IGFI-R dependent pathway(s).

We examined the ontogeny of mRNA levels of IGF-I and -II, IGF type 1 (IGFI-R) and type II receptors (IGFII-R), IGF binding protein-1 and -3 (IGFBP-1 and -3), GH receptor (GHR), and tissue concentrations of IGF and IGFBP in the pancreas of pigs. Tissues were collected from fetuses at 90 and 110 d of gestation and from pigs at 1, 21, 90 and 180 d of age. Northern blots were performed using total RNA hybridized with 32P-labeled cDNA probes (human IGF-I and human IGFI-R) and cRNA probes (rat IGF-II, human IGFII-R, human IGFBP-1, pig IGFBP-3, and pig GHR). There were two accelerated growth stages of the pancreas: the first one at 90 d of fetal life, which is characterized by cell hyperplasia (high ratio of DNA to body weight), and the second one at postnatal 90 d, which is attributed to cell hypertrophy (high ratios of pancreatic weight, RNA, and protein to DNA). The level of IGF-II mRNA and its tissue concentration were predominant during fetal life and low thereafter. The IGF-I mRNA level was high during fetal and early postnatal life and decreased thereafter. Messenger RNA levels of IGFI-R, IGFBP-3, and GHR and concentrations of IGFBP-1 and -2 were abundant during fetal and early postnatal life. In conclusion, IGF may be involved in various physiological periods of pancreatic development in pigs.

Insulin-like growth factors I and II (IGFI and II) are synthesized by anterior pituitary cells and participate in cellular growth and differentiation, as well as the control of pituitary hormone secretion. Type 1 and 2 IGF receptors (IGFR1 and IGFR2) and the six IGF binding proteins (IGFBPs), which modulate IGF effects, are expressed in the anterior pituitary gland. We used in situ hybridization to analyse the temporal expression pattern of IGFI and II, IGFR1 and 2 and IGFBP1-6 in the anterior pituitary gland during postnatal development in both male and female rats (10, 20, 30, 40 and 60 days of age). We found all of the components of the IGF system to be expressed in the anterior pituitary gland, with each having a specific temporal pattern of expression. In addition, there exist differences between the sexes in the expression of some components of the IGF system. These data emphasize that in the anterior pituitary gland the IGF system is under tight regulation during postnatal life when this gland continues to develop. The distinct temporal expression of each member of the IGF system may indicate specific roles in the development and physiology of the anterior pituitary gland.

The purpose of this study was to assess the validity of insulin-like growth factor (IGFI) determination as an index of nutritional status and growth in Equadorian schoolboys. Plasma IGFI was measured in 144 healthy boys, 9 years old, who were classified by their social class in four groups: 1 (n = 29); 2 (n = 49); 3 (n = 28); 4 (n = 8). Children in groups 1 and 2, of the lower socio-economic class, had significantly reduced caloric and protein intakes compared to children in groups 3 and 4 (P less than 0.01). Mean heights were significantly lower in groups 1 and 2 (P less than 0.001 and less than 0.05, respectively). The mean plasma IGFI in group 1 was 561 +/- 64 mU/ml and significantly lower than that in groups 2-4 (872 +/- 75, 986 +/- 94, and 1238 +/- 190 mU/ml in groups 2, 3 and 4, respectively) (P less than 0.01). The effect of caloric and nitrogen supplementation was studied in 36 children taken from groups 1 and 2 combined, and divided into three subgroups; they were given (1) an animal protein supplement of 18 g/day with 860 kcal/day (n = 12), (2) a vegetable protein supplement of 17.8 g/day based on a traditional Andean food with 862 kcal/day (n = 12), and (3) a placebo (n = 12). The IGFI levels increased significantly after 7 and 14 days in both subgroups 1 and 2. These results demonstrate that plasma IGFI reflects the nutritional status and responds to a short-term diet supplementation. It may provide a reliable means of assessing the effect of nutritional programs intended to improve the growth of children in underdeveloped countries.

Protein undernutrition is known to play an important role in the pathogenesis of osteoporotic fracture in elderly. The mechanisms underlying the bone loss in protein undernutrition appeared to be related to an uncoupling between increased bone resorption and bone formation. This was associated with decreased plasma IGF-I levels, with anoestrus and decreased muscle mass. Reversibility of protein undernutrition-induced bone loss was investigated in ovariectomized adult rats, which were fed isocaloric 2.5 % casein diet (OVX2.5) for 16 weeks. Then, the animals were given a supplement of essential amino-acids in similar proportion to that of casein at doses of 2.5% (EAA2.5) or 5% (EAA5) of total food intake for an additional 16 weeks. Essential amino acid supplements increased bone mineral mass and strength in ovariectomized protein-deprived rats. EAA supplements were associated with stimulated bone formation and reduced bone resorption, with increment of plasma IGF-I and of limb muscle mass weight. These results suggest that nutritional intervention with essential amino acid supplements can increase bone mineral mass, bone strength and muscle mass in osteoporotic rats possibly by correcting IGFI status.

OBJECTIVE

Low concentrations of insulin-like growth factor-I (IGFI) have been reported in type 1 diabetes mellitus (T1DM), suggested to be due to low insulin concentrations in the portal vein. The aim was to describe the long-term course of IGFI concentrations among T1DM subjects treated with continuous intraperitoneal (IP) insulin infusion (CIPII).

METHODS

Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF-I measurements were performed at the start of the 2006 study, after the 6 month SC- and CIPII treatment phase in 2006 and during CIPII therapy in 2012. Z-scores were calculated to compare the IGF-I concentrations with age-specific normative range values of a non-DM reference population.

RESULTS

In 2012, IGF-I Z-scores (-0.7; 95% confidence interval -1.3, -0.2) were significantly higher than at the start of the 2006 study (-2.5; -3.3, -1.8), the end of the SC (-2.0; -2.6, -1.5) and CIPII (-1.6; -2.1, -1.0) treatment phase with a mean difference of: 1.8 (0.9, 2.7), 1.3 (0.5, 2.1) and 0.8 (0.1, 1.6), respectively.

CONCLUSIONS

After 6 years of treatment with CIPII, IGF-I concentrations among T1DM patients increased to a level that is higher than during prior SC insulin treatment and is in the lower normal range compared to a non-DM reference population. The results of this study suggest that long-term IP insulin administration influences the IGF system in T1DM.

Short stature is a potential side-effect of BMT, brought about by the conditioning protocol and/or the complications of BMT. This study evaluates the effects of conditioning by chemotherapy, and BMT complications on growth. Thirty children conditioned for BMT by chemotherapy alone (cyclophosphamide and busulfan) were classified according to the occurrence of serious or prolonged complications after BMT: group 1 (n = 12) had no complication, while group 2 (n = 18) did. Fifteen of them were severely growth retarded (< or = -2 s.d.) at BMT, because of their initial disease. At the time of BMT, the two groups had similar ages (1.0 +/- 0.2, s.e.m. year, in group 1 and 1.7 +/- 0.5 year in group 2), height (-1.7 +/- 0.5; -1.8 +/- 0.3 s.d.) and plasma insulin-like growth factor I (IGFI) levels (0.3 +/- 0.1 U/ml in both). Group I grew significantly and their plasma IGFI increased but group 2 did not, as assessed 2 years post-BMT. We conclude that conditioning with chemotherapy alone does not prevent the catch-up growth induced by BMT in young children; the lack of catch-up growth is due to complications occurring after BMT, and the change in plasma IGFI suggests that complications of BMT prevent any increase in plasma IGFI, and thereby catch-up growth.

Intrauterine growth restriction (IUGR) is one of the major causes of short stature in childhood. Abnormalities in the growth hormone (GH) axis have frequently been observed in children who are born intrauterine growth restricted and GH treatment is effective to improve final height. However, the way that the GH axis is involved is not fully understood. Previously, when investigating the effect of IUGR on the central somatotrophic axis, a hypothalamic effect was discovered with elevated somatostatin and decreased neuropeptide Y mRNA expression levels, whereas serum GH and insulin-like growth factor I (IGFI) were unaltered. These findings were thought to indicate a hypothalamic alteration of the GH axis due to IUGR, probably to compensate pituitary output, thereby normalising peripheral values of GH and IGFI. Therefore, the present study aimed to evaluate the effect of IUGR on the pituitary GH axis in this rat model. Pups from rats that underwent bilateral uterine artery ligation at day 17 of pregnancy were studied. Pituitary glands were collected from 1-year-old offspring for quantitative measurements of GH, GH-receptor (GH-R), GH-releasing hormone receptor (GHRH-R), somatostatin receptor subtype 2 and 5, IGFI and IGFI receptor mRNA levels using a real-time reverse transcriptase-polymerase chain reaction. In addition, liver GH-R and IGFI mRNA expression levels were measured and a radioimmunoassay was performed to determine serum IGFI levels. In the IUGR rat, levels of pituitary GH, GH-R and GHRH-R relative gene expression (RGE) were increased. No differences were found in the RGE level of all other pituitary growth factors, liver GH-R and IGFI, and serum IGFI concentration between IUGR and control rats. The present data show that intrauterine growth failure leads to changes in the pituitary that might counterbalance the effects found previously in the hypothalamus.

BACKGROUND

The implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors. Up to now, suicide gene therapy has been the main experimental approach explored to treat experimental pituitary tumors. In the present study we assessed the effectiveness of insulin-like growth factor I (IGF-I) gene therapy for the treatment of estrogen-induced prolactinomas in rats.

RESULTS

Female Sprague Dawley rats were subcutaneously implanted with silastic capsules filled with 17-beta estradiol (E2) in order to induce pituitary prolactinomas. Blood samples were taken at regular intervals in order to measure serum prolactin (PRL). As expected, serum PRL increased progressively and 23 days after implanting the E2 capsules (Experimental day 0), circulating PRL had undergone a 3-4 fold increase. On Experimental day 0 part of the E2-implanted animals received a bilateral intrapituitary injection of either an adenoviral vector expressing the gene for rat IGF-I (RAd-IGFI), or a vector (RAd-GFP) expressing the gene for green fluorescent protein (GFP). Seven days post vector injection all animals were sacrificed and their pituitaries morphometrically analyzed to evaluate changes in the lactotroph population. RAd-IGFI but not RAd-GFP, induced a significant fall in serum PRL. Furthermore, RAd-IGFI but not RAd-GFP significantly reversed the increase in lactotroph size (CS) and volume density (VD) induced by E2 treatment.

CONCLUSIONS

We conclude that IGF-I gene therapy constitutes a potentially useful intervention for the treatment of prolactinomas and that bioactive peptide gene delivery may open novel therapeutic avenues for the treatment of pituitary tumors.

Leptin, insulin, ghrelin, and IGF-I are circulating peptide hormones concerned with energy homeostasis and the regulation of GH axis. They are present in human milk, and are thought to promote neonatal development. The aim of the present study was to detect these substances in goat milk and determine whether their levels can be modified by changing the macronutrient content of the lactating animals' diet. Sixteen Saanen goats in mid-lactation were divided into two balanced groups, one given a diet containing 17% starch (LS) and the other a diet of 33% starch (HS). Eighty days later, leptin, insulin, ghrelin, and IGF-I were determined by human radioimmunoassay kits in plasma before and after feeding, and in sonicated milk centrifuged to remove fat from morning and evening milking. The HS diet was associated with higher plasma and milk insulin and IGF-I, and plasma ghrelin. Leptin, insulin, and ghrelin in milk were two-three times higher than in plasma; milk IGF-I was only 5-20% of plasma level. Plasma insulin correlated positively with plasma IGF-I; morning milk IGFI and insulin correlated positively with morning plasma levels. These findings demonstrate that human immuno-activities of bioactive peptides are present in goat milk, and also that levels of insulin and IGF-I in milk can be altered by changing the macronutrient content of the diet. Further research is required to determine whether these substances can be transferred from the milk to suckling animals and humans, and whether they have biological activity in such animals.

Tremendous strides have been made in improving patients' survival from cancer with one glaring exception: brain cancer. Glioblastoma is the most common, aggressive and highly malignant type of primary brain tumor. The average overall survival remains less than 1 year. Notably, cancer patients with obesity and diabetes have worse outcomes and accelerated progression of glioblastoma. The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway. However, while the process of invasive glioblastoma progression has been extensively studied macroscopically, it has not yet been well characterized with regards to intracellular insulin signaling. In this study we connect for the first time microscale insulin signaling activity with macroscale glioblastoma growth through the use of computational modeling. Results of the model suggest a novel observation: feedback from IGFBP2 to HIF1α is integral to the sustained growth of glioblastoma. Our study suggests that downstream signaling from IGFI to HIF1α, which has been the target of many insulin signaling drugs in clinical trials, plays a smaller role in overall tumor growth. These predictions strongly suggest redirecting the focus of glioma drug candidates on controlling the feedback between IGFBP2 and HIF1α.

BACKGROUND

Infantile anorexia nervosa (AN) is a specific eating disorder of prepubertal children. Poor data are available on growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in this disorder.

METHODS

We report on a boy (4.5 years) with progressive growth impairment. At psychiatric assessment (DC: 0-3 R, AXIS I), he fulfilled all required criteria for diagnosis of infantile AN. Endocrine evaluation suggested impaired peripheral response to GH (high GH and low IGF-1 levels), likely related to energy deficiency.

METHODS

Auxological evaluation was shown as raw data and SDS using Italian reference values. GH secretion was assessed by arginine provocative test; IGFI generation test was done administering recombinant GH (0.05 mg/kg/day for four days). Psychiatric assessment was performed according to the DC:0-3R protocol.

CONCLUSIONS

Impaired GH-IGF-1 axis may be involved in growth delay of children with infantile AN. A strict collaboration between endocrine pediatricians and child psychiatrists is advisable in the assessment of poor growing children without recognizable organic causes, showing normal/high GH levels and low IGF-1 values.

OBJECTIVE

To evaluate the physiological role of insulin-like growth factor-I (IGFI) and its interaction with gonadotropins in cell replication of two types of granulosa cells (cumulus oophorus, CC) and mural granulosa cells (MGC).

METHODS

Controlled randomized study of the action and interaction of gonadotropins and IGFI on granulosa cell replication in the rat.

METHODS

A university reproductive biology laboratory.

METHODS

The study examined the in vivo treatment with gonadotropins or an analogue of IGFI, long Arg3-insulin-like growth factor (LR3-IGFI), which does not bind to IGFI-binding proteins.

METHODS

Granulosa cell replication was evaluated by the use of 3H-thymidine incorporation.

RESULTS

It was noted that the CC replicate much faster than the MGC. These two types of granulosa cells have very different dose response curves to IGFI. Differential responses were seen in animal cells exposed to long Arg3-insulin-like growth factor in vivo and then exposed to FSH and LH in vitro.

CONCLUSIONS

Although murine granulosa cells show proliferative activity when they are exposed to IGFI, the two types, CC and MGC, respond differently. IGFI is not the sole mediator of the action of FSH, and these two chemicals may act independently or in concert.

BACKGROUND

Through overexpression and aberrant activation in many human tumors, the IGF system plays a key role in tumor development and tumor cell proliferation. Different strategies targeting IGF-I receptor (IGFI-R) have been developed, and recent studies demonstrated that combined treatments with cytostatic drugs enhance the potency of anti-IGFI-R therapies.

OBJECTIVE

The objective of the study was to examine the IGFI-R expression status in neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) in comparison with healthy tissues and use potential overexpression as a target for novel anti-IGFI-R immunoliposomes.

METHODS

A human tumor tissue array and samples from different normal tissues were investigated by immunohistochemistry. An IGFI-R antagonistic antibody (1H7) was coupled to the surface of sterically stabilized liposomes loaded with doxorubicin. Cell lines from different tumor entities were investigated for liposomal association studies in vitro. For in vivo experiments, neuroendocrine tumor xenografts were used for evaluation of pharmacokinetic and therapeutic properties of the novel compound.

RESULTS

Immunohistochemistry revealed significant IGFI-R overexpression in all investigated GEP-NETs (n = 59; staining index, 229.1 +/- 3.1%) in comparison with normal tissues (115.7 +/- 3.7%). Furthermore, anti-IGFI-R immunoliposomes displayed specific tumor cell association (44.2 +/- 1.6% vs. IgG liposomes, 0.8 +/- 0.3%; P < 0.0001) and internalization in human neuroendocrine tumor cells in vitro and superior antitumor efficacy in vivo (life span 31.5 +/- 2.2 d vs. untreated control, 19 +/- 0.6, P = 0.008).

CONCLUSIONS

IGFI-R overexpression seems to be a common characteristic of otherwise heterogenous NETs. Novel anti-IGFI-R immunoliposomes have been developed and successfully tested in a preclinical model for human GEP-NETs. Moreover in vitro experiments indicate that usage of this agent could also present a promising approach for other tumor entities.

Anthocyanins are known cyto-protective agents against various stress conditions. In this study cardio-protective effect of anthocyanins from black rice against diabetic mellitus (DM) was evaluated using a streptozotocin (STZ)-induced DM rat model. Five-week-old male Wistar rats were administered with STZ (55 mg kg-1 , IP) to induce DM; rats in the treatment group received 250 mg oral anthocyanin/kg/day during the 4-week treatment period. DM and the control rats received normal saline through oral gavage. The results reveal that STZ-induced DM elevates myocardial apoptosis and associated proapoptotic proteins but down-regulates the proteins of IGF1R mediated survival signaling mechanism. Furthermore, the functional parameters such as the ejection-fraction and fraction-shortening in the DM rat hearts declined considerably. However, the rats treated with anthocyanins significantly reduced apoptosis and the associated proapoptotic proteins and further increased the survival signals to restore the cardiac functions in DM rats. Anthocyanin supplementation enhances cardiomyocyte survival and restores cardiac function.

BACKGROUND

Insulin-like growth factor I (IGF-I) and other markers of insulin resistance (IRm) might influence the penetrance of BRCA gene mutation. In a demonstration project on BRCA mutation carriers we tested the effect of the 'Mediterranean diet', with moderate protein restriction, on serum levels of IGF-I and IRm.

METHODS

BRCA mutation carriers, with or without breast cancer, aged 18⁻70 years and without metastases were eligible. After the baseline examinations, women were randomized to an active dietary intervention or to a control group. The intervention group attended six full days of life-style intervention activities (cookery classes followed by lunch, sessions of walking for 45 min and nutritional conferences) over the next six months.

RESULTS

213 BRCA mutation carriers completed the six-month study. Women in the intervention group (110) showed major changes in all the parameters under study. They significantly lost weight (p < 0.001), fat mass (p = 0.002), with reduced hip circumference (p = 0.01), triglycerides (p = 0.02) and IGF-I (p = 0.02) compared with controls. They also had a significantly higher levels of insulin-like growth factor-binding protein 3 (IGFI-BP3) (p = 0.03) and a lower IGF-I/IGFI-BP3 ratio (p = 0.04). The reduction of serum levels of IGF-I was significantly associated with the reduction in the consumption of animal products (p = 0.04).

CONCLUSIONS

Women in the intervention group showed significant improvements in IGF-I and in other IRm that might influence the penetrance of BRCA mutations.