Including Insulin-like Growth Factor 1 Research Articles

Manipulation of the Growth Hormone-Insulin-Like Growth Factor (GH-IGF) Axis: A Treatment Strategy to Reverse the Effects of Early Life Developmental Programming.

Evidence from human clinical, epidemiological, and experimental animal models has clearly highlighted a link between the early life environment and an increased risk for a range of cardiometabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and overnutrition, spanning exposure windows that cover the period from preconception through to early infancy, clearly highlight an increased risk for a range of disorders in offspring in later life. This process, preferentially termed “developmental programming” as part of the developmental origins of health and disease (DOHaD) framework, leads to phenotypic outcomes in offspring that closely resemble those of individuals with untreated growth hormone (GH) deficiency, including increased adiposity and cardiovascular disorders. As such, the use of GH as a potential intervention strategy to mitigate the effects of developmental malprogramming has received some attention in the DOHaD field. In particular, experimental animal models have shown that early GH treatment in the setting of poor maternal nutrition can partially rescue the programmed phenotype, albeit in a sex-specific manner. Although the mechanisms remain poorly defined, they include changes to endothelial function, an altered inflammasome, changes in adipogenesis and cardiovascular function, neuroendocrine effects, and changes in the epigenetic regulation of gene expression. Similarly, GH treatment to adult offspring, where an adverse metabolic phenotype is already manifest, has shown efficacy in reversing some of the metabolic disorders arising from a poor early life environment. Components of the GH-insulin-like growth factor (IGF)-IGF binding protein (GH-IGF-IGFBP) system, including insulin-like growth factor 1 (IGF-1), have also shown promise in ameliorating programmed metabolic disorders, potentially acting via epigenetic processes including changes in miRNA profiles and altered DNA methylation. However, as with the use of GH in the clinical setting of short stature and GH-deficiency, the benefits of treatment are also, in some cases, associated with potential unwanted side effects that need to be taken into account before effective translation as an intervention modality in the DOHaD context can be undertaken.

New Insights into the Function of TRPV Channels

Transient receptor potential vanilloid 2 (TRPV2) is a non-selective Ca2+-permeable cation channel that belongs to the vanilloid subfamily of the TRP superfamily. Despite its discovery as a thermoTRPV channel over 15 years ago, TRPV2 remains an “orphan TRP” due to its still unclear physiological function. Here we took advantage of our ability to generate stable, functional recombinant TRPV2 to gain new biological insights into the cellular function of TRPV2. Using tetrameric TRPV2 as an antigen, we generated TRPV2 monoclonal antibodies and used these antibodies to test the controversial hypothesis that growth factors, including insulin-like growth factor 1 (IGF-1), cause translocation of TRPV2 to the plasma membrane. We found that TRPV2 localizes to intracellular membranes in both the absence and presence of growth factors in multiple cell types. Additionally, we used these newly generated antibodies to explore the role of TRPV2 in neuronal cell development. A detailed analysis revealed that nerve growth factor (NGF) increases TRPV2 expression through the MAPK signaling pathway. Furthermore, we discovered TRPV2 acts as a novel ERK substrate, whereby phosphorylation of TRPV2 by ERK enhances TRPV2-mediated Ca2+ signals and neurite outgrowth downstream of NGF. TRPV2 localizes to endosomal pools within neurites of developing neurons, where it may serve to alter local Ca2+ signals. Based on these data, we propose a previously uncharacterized mechanism in which TRPV2 acts as an endosomal Ca2+ channel regulated by NGF via the MAPK pathway to alter local Ca2+ signaling within neurites and enhance neurite outgrowth.

Effect of Early Expressed Human Milk on Insulin-Like Growth Factor 1 and Short-Term Outcomes in Preterm Infants.

AimsPreterm breast milk contains high levels of bioactive components, including insulin-like growth factor 1 (IGF-1), that are reduced by Holder pasteurization. Animal studies have shown that milk-borne IGF-1 is likely absorbed intact in a bioactive form by the intestines. The aim of this study was to assess if early non-pasteurized expressed breast milk nutrition may affect IGF-1 plasma levels in premature infants. We also investigated the possible association between early expressed milk nutrition and short-term outcomes.MethodsFifty-two preterm infants with gestational age < 31 weeks were divided into two groups according to expressed breast milk intake (< or ≥ 50 mL/Kg/day) until 32 weeks of postmenstrual age when blood sampling for IGF-1 analysis was performed.ResultsIn our population, early expressed breast milk does not affect IGF-1 plasma levels (p 0.48). An association was observed between early expressed milk nutrition and a lower incidence of bronchopulmonary dysplasia, sepsis, feeding intolerance, need for parenteral nutrition and length of hospitalization.ConclusionsContrary to the results in some animal studies, our results did not seem to show that early expressed breast milk can help to maintain postnatal IGF-1 near foetal levels in preterm infants. The observed protective effect of expressed breast milk on short-term outcomes can be the starting point for further study of the effects of non-pasteurized human milk in preterm infants.

Growth Hormone Receptor (GHR) gene and its applicationsin livestock: A review

The Growth Hormone Receptor (GHR) gene provides instructions for making a protein called the growth hormone receptor. The GHR mediates biological actions of growth hormone on target cells by transducing the growth hormone (GH) signal across the cell membrane and inducing transcription of many genes, including insulin-like growth factor-1 (IGF1). The gene coding for bovine GHR gene consists of nine exons. In exon 8 of the bovine GHR gene, T/A nucleotide variation results in to change in tyrosine from phenylalanine in the transmembrane domain of the GHR protein, has been reported to be associated with a major effect on milk yield in cows. GHR (growth hormone receptor) gene has been shown to harbor a causal mutation of a QTL influencing milk yield and composition GHR gene is a polymorphic gene and the polymorphisms are related to different economic traits of different species. The GHR gene influences physical traits and helps to selection of animals. The lengths of the variable TG-repeats in the P1 promoter of the bovine GHR gene are associated with growth rates in young Angus cattle. Due to various functions of GHR are viewed as promising candidate markers for selection purposes in cattle. Thus GHR gene could be a candidate gene for application in marker assisted selection (MAS).

Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function.

The mechanism by which stem cell-based therapy improves heart function is still unknown, but paracrine mechanisms seem to be involved. Adipose-derived stem cells (ADSCs) secrete several factors, including insulin-like growth factor-1 (IGF-1), which may contribute to myocardial regeneration. Our aim was to investigate whether the overexpression of IGF-1 in ADSCs (IGF-1-ADSCs) improves treatment of chronically infarcted rat hearts. ADSCs were transduced with a lentiviral vector to induce IGF-1 overexpression. IGF-1-ADSCs transcribe100- to 200-fold more IGF-1 mRNA levels compared to nontransduced ADSCs. IGF-1 transduction did not alter ADSC immunophenotypic characteristics even under hypoxic conditions. However, IGF-1-ADSCs proliferate at higher rates and release greater amounts of growth factors such as IGF-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) under normoxic and hypoxic conditions. Importantly, IGF-1 secreted by IGF-1-ADSCs is functional given that Akt-1 phosphorylation was remarkably induced in neonatal cardiomyocytes cocultured with IGF-1-ADSCs, and this increase was prevented with phosphatidylinositol 3-kinase (PI3K) inhibitor treatment. Next, we tested IGF-1-ADSCs in a rat myocardial infarction (MI) model. MI was performed by coronary ligation, and 4 weeks after MI, animals received intramyocardial injections of either ADSCs (n = 7), IGF-1-ADSCs (n = 7), or vehicle (n = 7) into the infarcted border zone. Left ventricular function was evaluated by echocardiography before and after 6 weeks of treatment, and left ventricular hemodynamics were assessed 7 weeks after cell injection. Notably, IGF-1-ADSCs improved left ventricular ejection fraction and cardiac contractility index, but did not reduce scar size when compared to the ADSC-treated group. In summary, transplantation of ADSCs transduced with IGF-1 is a superior therapeutic approach to treat MI compared to nontransduced ADSCs, suggesting that gene and cell therapy may bring additional benefits to the treatment of MI.

Low-intensity exercise training maintains adipokines in obese children

The aim of the present study is to investigate the effects of a 12 weeks low-intensity exercise training on body composition, adipokines, and growth factors in normal (NG) and obese (OG) children. Maximal oxygen uptake (VO 2 max); body composition; adipokines consisting of adiponectin, retinol binding protein-4 (RBP4), and interleukin-6 (IL-6); and growth factors including insulin like growth factor-1 (IGF-1) and insulin like growth factor binding protein-3 (IGF-BP3) were measured before and after low-intensity exercise training program. Body composition parameters such as body weight, body mass index, body fat (%) and VO2 max were significantly different between NG and OG. Adiponectin levels in NG were increased after 12 weeks exercise training. In addition, our results showed that the concentrations of adiponectin, RBP4, IGF-1, and IGF-BP3 in OG were higher than those of NG. Adiponectin levels were significantly correlated with body fat ( r = −0.545, p = 0.001) and VO 2 max ( r = 0.368, p = 0.032) and RBP4 levels were significantly correlated with body fat ( r = 0.371, p = 0.031) in all subjects. Exercise training improved adiponectin levels in NG subjects and maintained the levels of body fat, adipokines (adiponectin, RBP4), and growth factors (IGF-1, IGF-BP3) in OG subjects. The present study revealed that regular low-intensity exercise training is strongly associated with high adiponectin levels in healthy children. However, obese children did not exhibit any changes in the levels of adipokines and maintained body composition and growth factors.

Evidence for Ligand-Independent Activation of Hippocampal Estrogen Receptor-α by IGF-1 in Hippocampus of Ovariectomized Rats.

In the absence of ovarian estrogens, increased levels of estrogen receptor (ER)α in the hippocampus are associated with improvements in cognition. In vitro evidence indicates that under conditions of low estrogen, growth factors, including Insulin-Like Growth Factor 1 (IGF-1), can activate ERα and regulate ERα-mediated transcription through mechanisms that likely involve modification of phosphorylation sites on the receptor. The goal of the current work was to investigate a role for IGF-1 in ligand-independent activation of ERα in the hippocampus of female rats. Ovariectomized rats received a single intracerebroventricular infusion of IGF-1 and hippocampi were collected 1 or 24 hours later. After 1 h, IGF-1 increased hippocampal levels of phosphorylated ERα at serine 118 (S118) as revealed by Western blotting. Coimmunoprecipitation revealed that at 1 hour after infusion, IGF-1 increased association between ERα and steroid receptor coactivator 1, a histone acetyltransferase that increases transcriptional activity of phosphorylated ERα. IGF-1 infusion increased levels of the ERα-regulated proteins ERα, choline acetyltransferase, and brain-derived neurotrophic factor in the hippocampus 24 hours after infusion. Results indicate that IGF-1 activates ERα in ligand-independent manner in the hippocampus via phosphorylation at S118 resulting in increased association of ERα with steroid receptor coactivator 1 and elevation of ER-regulated proteins. To our knowledge, these data are the first in vivo evidence of ligand-independent actions of ERα and provide a mechanism by which ERα can impact memory in the absence of ovarian estrogens.

Puerarin affects bone biomarkers in the serum of rats with intrauterine growth restriction

ObjectiveTo investigate serum bone biomarkers in rats with intrauterine growth restriction (IUGR) in order to determine the effects of puerarin on bone metabolism. MethodsA rat model of IUGR was induced using a low protein diet during pregnancy. The offspring were given puerarin or an identical volume of saline via subcutaneous abdominal injection. All rats were studied at 1,3, and 8 weeks of age. Serum biomarkers of bone formation, including insulin-like growth factor-1 (IGF-1), bone-specific alkaline phosphatase (BALP), osteocalcin (OC), osteoprotegerin (OPG), receptor-activator of nuclear factor-KB ligand (RANKL), as well as blood levels of calcium and phosphorus were measured. ResultsSerum BALP, OPG, IGF-1, and OC levels, as well as the OPG/RANKL ratio, were lower in the IUGR group compared with the control group at 1 week of age (P = 0.024, 0.011, 0.014, 0.004, and 0.002, respectively). At 3 weeks of age, the serum BALP and OC levels were higher in the protein-restricted group compared with the control group (P = 0.003 and 0.001, respectively). A comparison between the IUGR plus puerarin intervention group and the IUGR group revealed differences in the levels of BALP and IGF-1 at 3 weeks of age (P = 0.008 and 0.003, respectively). In addition, serum OPG and OC levels and the OPG/RANKL ratio were higher at 8 weeks of age (P = 0.044, 0.007, and 0.016, respectively). No differences in serum calcium and phosphorus levels were observed among the three groups. ConclusionOur study demonstrates that the bone microenvironment of the fetus can be altered by a low protein maternal diet and that puerarin can reverse these effects. These results indicate that the nutritional environment plays an important role in early skeletal development and that the bone turnover of IUGR rats can be altered by puerarin treatment.

Identification of microRNA and target gene associated with marbling score in Korean cattle (Hanwoo)

Marbling is a crucial characteristic in meat quality assessment. In the search for a genetic basis of meat quality, a large number of gene analyses seeking to find loci for a marbling trait have already been reported. However, the influence of microRNA (miRNA) on expression patterns and their ultimate influence on marbling is poorly understood. To better understand post-transcriptional influences on marbling, we applied a microarray analysis to measure the relationship between marbling scores and miRNA and messenger RNA expression in Hanwoo longissimus muscle tissue. Our results build correlations between miRNAs and differentially expressed genes and pathways. Our microarray analysis identified 763 genes and 11 miRNAs that are differentially expressed relative to marbling score. Overall, upregulated miRNAs were associated with downregulated genes. Fifteen genes targeted by miRNAs including insulin-like growth factor 1 (IGF-1) and kruppel-like factor 11 (KLF11), which regulate fatty acid synthase and lipid metabolism. And the expression levels of KLF11 and bta-miR-494 were validated. The results show that downregulated bta-miR-494 was associated with the upregulation of KLF11 gene. Among the differentially expressed genes found to be associated with the marbling score, we identified 15 genes targeted by miRNAs. Furthermore, the expression patterns of the genes KLF11, and bta-miR-494, may influence marbling in Hanwoo.

Early midtrimester serum insulin-like factors and cervical length to predict preterm delivery

ObjectiveTo investigate which ultrasound findings or serum biomarkers, including insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 and 3 (IGFBP-1 and IGFBP-3, respectively), in the first and early second trimesters are the best predictors for preterm delivery. Materials and MethodsThis was a case–control study conducted between March 2011 and March 2013 with women presenting for routine antenatal care at 11–18 weeks. We collected serum samples from pregnant women and stored them at −80°C. All patients underwent cervical length (CL) measurement at 18–21 weeks. We retrieved frozen samples for analysis from women with subsequent preterm and term delivery. Prediction models were developed using multivariate stepwise logistic regression. Receiver-operating characteristics curves were used to determine the most useful cutoff point. ResultsOf the 72 women recruited, 24 women underwent spontaneous preterm delivery, and 48 women with term delivery were randomly selected as the control group, in a 1:2 ratio. The maternal serum concentration of IGFBP-3 and CL were significantly associated with preterm birth. ConclusionAmong the various known ultrasound findings and serum biomarkers in the early midtrimester, only CL and IGFBP-3 are independent predictors for preterm delivery in asymptomatic women.

EP01.15: Cervical length and early mid‐trimester serum insulin‐like factors to predict preterm delivery

This study aimed to investigate which ultrasound findings or serum biomarkers, including insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 and 3 (IGFBP-1 and IGFBP-3), in the first and early second trimesters are the best predictors for preterm delivery. This was a case–control study conducted between March 2011 and March 2013 with women presenting for routine antenatal care at 11–18 weeks. We collected serum samples from pregnant women and stored them at −80 °C. All patients underwent cervical length measurement at 18–21 weeks. We retrieved frozen samples for analysis from women with subsequent preterm and term delivery. Prediction models were developed using multivariate stepwise logistic regression. Receiver-operating characteristics curves were used to determine the most useful cutoff point. Of the 72 women recruited, 24 women (33%) underwent spontaneous preterm delivery and 48 women with term delivery were randomly selected as the control group, in a 1:2 ratio. The maternal serum concentration of IGFBP-3 and cervical length were significantly associated with preterm birth. Among the various known ultrasound findings and serum biomarkers in the early mid-trimester, only cervical length and IGFBP-3 are independent predictors for preterm delivery in asymptomatic women.

Somatotrope GHRH/GH/IGF-1 axis at the crossroads between immunosenescence and frailty.

Immunosenescence, characterized by complex modifications of immunity with age, could be related to frailty syndrome in elderly individuals, leading to an inadequate response to minimal aggression. Functional decline (i.e., the loss of ability to perform activities of daily living) is related to frailty and decreased physiological reserves and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty have been explored and 20 immunological parameters, including insulin-like growth factor-1 (IGF-1), thymopoeisis, and telomere length, were shown to be affected in elderly patients with functional decline. A strong relationship between IGF-1 and thymic ouput was evidenced. IGF-1, a mediator of growth hormone (GH), was subsequently shown to induce interleukin-7 secretion in cultured primary human thymic epithelial cells. We are exploring the stress hypothesis in which an acute stressor is used as the discriminator of frailty susceptibility. GH can counteract the deleterious immunosuppressive effects of stress-induced steroids. Under nonstress conditions, the immunosenescent system preserves physiological responses, while under stress conditions, the combination of immunosenescence and a defect in the somatotrope axis might lead to functional decline.

Effect of light-emitting-diode irradiation on the proliferation and migration in human gingival fibroblasts

Purpose The aim of this study is to evaluate proliferation, migration, and various gene expressions including insulin-like growth factor 1 (IGF-1), SMAD3, and collagen type I (COL1A1) during light-emitting diode (LED) irradiation of human gingival fibroblasts (HGF).

Integrin αvβ3 mediates the synergetic regulation of core-binding factor α1 transcriptional activity by gravity and insulin-like growth factor-1 through phosphoinositide 3-kinase signaling

Mechanical stimulation and biological factors coordinately regulate bone development and regeneration; however, the underlying mechanisms are poorly understood. Microgravity induces bone loss, which may be partly related to the development of resistance to local cytokines, including insulin-like growth factor 1 (IGF-1). Here, we report the involvement of integrin αvβ3 in microgravity-associated bone loss. An established OSE-3T3 cell model was stably transfected with a 6OSE2 (Osteoblast-Specific Element 2)-luciferase reporter and cultured under simulated microgravity (SMG) and hypergravity (HG) conditions in the presence or absence of IGF-1, the disintegrin echistatin, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, or combinations of these agents. Activity of core-binding factor α1 (Cbfa1), an essential transcription factor for osteoblastic differentiation and osteogenesis, was reflected by luciferase activity. Different gravity conditions affected the induction of IGF-1 and subsequent effects on Cbfa1 transcription activity. SMG and HG influenced the expression and activity of integrin αvβ3 and phosphorylation level of p85. LY294002 inhibited the effects of HG or IGF-1 on Cbfa1 activity, indicating that HG and IGF-1 could increase Cbfa1 activity via PI3K signaling. Inhibition of integrin αvβ3 by echistatin attenuated the induction of IGF-1 and thus its effect on Cbfa1 activity under normal and HG conditions. Co-immunoprecipitation demonstrated that integrin β3 interacted with insulin receptor substrate 1, and that this interaction was decreased under SMG and increased under HG conditions. These results suggest that integrin αvβ3 mediates the synergetic regulation of Cbfa1 transcription activity by gravity and IGF-1 via PI3K signaling.

Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways.

Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.

Sleep quality, BDNF genotype and gene expression in individuals with chronic abdominal pain

BackgroundSleep quality and genetics may contribute to the etiology of gastrointestinal (GI) symptoms. Individuals with impaired sleep often have a number of associated symptoms including chronic abdominal pain (CAP). The current study examined the interactions of brain-derived neurotrophic factor (BDNF) genotype with sleep quality in persons with CAP and healthy controls. In addition, associations among sleep quality, BDNF genotype, and gene expression were explored in the participants.MethodsData were collected on 59 participants (46% male, 61% White, 26.9 ± 6.6 years; CAP (n=19) and healthy controls (n=40)). Participants with CAP reported poorer sleep quality compared to healthy controls. BDNF genotype, categorized as Val/Val homozygotes versus the Met carriers.ResultsMicroarray analysis found twenty-four differentially expressed genes by a two-fold magnitude in participants with poor sleep quality compared to good sleep quality, and seven differentially expressed genes comparing CAP to healthy control. Three specific genes in the pain group overlap with sleep quality, including insulin-like growth factor 1 (IGF1), spermatogenesis associated serine-rich 2-like (SPATS2L), and immunoglobulin heavy constant gamma 1 or mu (IGHG1/// IGHM). BDNF was shown to have an interaction effect with GI and sleep symptoms.ConclusionsParticipants with CAP reported poor sleep quality compared to healthy controls. The role of the BDNF Met allele on differential gene expression was not distinct as main factor, but impacted interactions with sleep quality and CAP. Down-regulation of IGF1, SPATS2L, and IGHG1 expression may be related to the etiology of poor sleep quality and CAP.Trial registrationClinicaltrial.gov # NCT00824941

Competing risks of death in younger and older postmenopausal breast cancer patients

To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models. The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality. We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

Maternal Infection with Schistosoma japonicum Induces a Profibrotic Response in Neonates

The global burden of schistosomiasis is significant, with fibrosis a major associated morbidity and the primary cause of mortality. We have previously shown that schistosomiasis during pregnancy upregulates proinflammatory cytokines in the cord blood. In this study, we extend these findings to include a large panel of fibrosis-associated markers. We developed a multiplex bead-based assay to measure the levels of 35 proteins associated with fibrosis. Cord blood from 109 neonates born to mothers residing in an area of Schistosoma japonicum endemicity was assessed for these molecules. Ten mediators were elevated in the cord blood from schistosome-infected pregnancies, including insulin-like growth factor 1 (IGF-1), tumor growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), procollagen I carboxy-terminal propeptide (PICP), amino-telopeptide of type 1 collagen (ICTP), collagen VI, desmosine, matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1), and TIMP-4. Many of these were also positively correlated with preterm birth (PICP, ICTP, MMP-2, TGF-β1, desmosine, CTGF, TIMP-1). In addition, birth weight was 168 g lower for infants with detectable levels of CTGF than for those with CTGF levels below the level of detection. Maternal schistosomiasis results in upregulation of fibrosis-associated proteins in the cord blood of the neonate, a subset of which are also associated with adverse birth outcomes. As the first report of fibrosis-associated molecules altered in the newborn of infected mothers, this study has broad implications for the health of the fetus, stretching from gestation to adulthood.

Reconditioning effect of oligodendrocyte-like cell transplantation in acute spinal cord injury in rats

To observe the reconditioning effect of oligodendrocyte-like cell transplantation in acute spinal cord injury in rats, bone marrow mesenchymal stem cells were differentiated into oligodendrocyte-like cells induced by cytokines including insulin-like growth factor-1(IGF-1). Rats with acute spinal cord injury were treated with the oligodendrocyte-like cells for 8 weeks by local injection. The therapeutic effect was compared with oligodendrocytes transplantation and saline. Regeneration of axon myelin sheath and functional recovery of hind limbs were significantly improved after transplantation with oligodendrocyte-like cells than that with saline. But there was no significant difference between rats treated with oligodendrocyte-like cells and oligodendrocytes. Bone marrow mesenchymal stem cells differentiating into oligodendrocyte-like cells can be induced by cytokines including IGF-1, with similar specific surface markers of oligodendrocytes. These cells can survive in injury sites of the spinal cord for a long duration after transplantation to improve recovery of neural function and reduce cavity area at injury site after acute spinal injury in rats. The possible mechanism may be regeneration of axon myelin sheath, which is helpful for reconstruction of neural reflex function. Key words: Oligodendrocyte-like cells, differentiation, spinal cord injury, transplantation.

Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer

MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.