The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added 125 I-hIGFBP-2 specifically bound to the cells. Bound 125 I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for 5 1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P<0·01), and of the p42/44 MAP-kinases of up to 40% (P<0·01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P<0·05), and reduced proliferation by 24% (P<0·01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with 5 1-integrin.

Background: Formula milk-fed infants show faster rates of growth and weight gain than do breastfed infants, and they have higher concentrations of insulin-like growth factor I (IGF-I). Objective: Our objective was to determine the influence of IGF-I concentrations on gains in weight, length, body mass index (BMI), and adiposity in the first year of life. Design: IGF-I concentrations were measured in 953 capillary blood samples from 675 unselected infants at ages 3 and 12 mo. These infants were born between 2002 and 2008 in one center and were participating in a prospective longitudinal birth cohort. Weight, length, and 4 skinfold thicknesses as an indicator of adiposity were measured at ages 0, 3, and 12 mo. Analyses were adjusted for age and sex. Results: Infants who were formula milk-fed had higher IGF-I concentrations at 3 mo, and they showed greater gains in weight, length, BMI, and adiposity between age 3 and 12 mo. IGF-I concentrations at 3 mo were unrelated to subsequent overall weight gain (P = 0.5). However, higher IGF-I concentrations at age 3 mo predicted greater subsequent gains in body length (P , 0.001 and P = 0.007 in formula milk-fed and breastfed infants, respectively) and slower gains in BMI (P , 0.001 and P = 0.004, respectively) and adiposity (P = 0.03 and P = 0.003, respectively). Conclusions: Our findings support a key role for IGF-I in the partitioning of overall infant weight gain into statural growth compared with adiposity. In formula milk-fed infants, higher IGF-I concentrations may lead to faster gains in length; however, other mechanisms likely explain their faster gains in weight, BMI, and adiposity. Am J Clin Nutr 2009;90:156-61.

BackgroundThere is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.MethodsWe assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.ResultsA large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.ConclusionsConcomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.

There is increasing evidence that in Lewy body-associated dementias (encompassing Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB)), the adaptive immune system is altered and the degenerative process includes glial cells in addition to neuronal structures. We therefore aimed to determine levels of autoantibodies against amyloid and glial-derived structures in these dementia types. Using a newly developed Enzyme-linked immunosorbent assay (ELISA), we measured levels of IgG autoantibodies against neuronal and glial structures in serum and cerebrospinal fluid of a total of 91 subjects (13 PDD, 14 DLB, 11 Alzheimer's disease (AD), 11 frontotemporal dementia (FTD), 11 vascular dementia patients (VaD), and 31 healthy controls). Autoantibody levels against α-synuclein, amyloid-β₄₂ (Aβ₄₂), myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and S100B were determined. In all groups, autoantibody levels were about three magnitudes higher in serum than in CSF. Serum autoantibody levels against α-synuclein, Aβ₄₂, MOG, MBP, and S100B were higher in PDD/DLB compared to tau-associated dementias (AD, FTD), VaD, and controls, respectively, with most of them reaching highly significant p-values. In cerebrospinal fluid (CSF), levels of antibodies against oligodendrocyte-derived antigens (MOG, MBP) were significantly increased in PDD/DLB. Increased levels of autoantibodies against both neuronal- and glial-derived antigens in serum and CSF of Lewy body-associated dementias indicate an altered activity of the adaptive immune system in these dementia types. The potential of neural-derived IgG autoantibodies as part of a biomarker panel for the diagnosis of Lewy body-associated dementias should be further evaluated.

To elucidate the functional importance of transmembrane domain II in the Na ؉ /proline transporter (PutP) of Escherichia coli we analyzed the effect of replacing Ser-54 through Gly-58. Substitution of Asp-55 or Met-56 dramatically reduces the apparent affinity for Na ؉ and Li ؉ in a cation-dependent manner. Conversely, Cys in place of Gly-58 significantly reduces only the apparent proline affinity while substitution of Ser-57 results in a dramatic reduction of the apparent proline and cation affinities. Interestingly, upon increasing the proline concentration the apparent Na ؉ affinity of Ser-57 replacement mutants converges toward the wild-type value, indicating a close cooperativity between cation and substrate site(s). This notion is supported by the fact that Na ؉ -stimulated site-specific fluorescence labeling of a single Cys at position 57 is completely reversed by the addition of proline. Similar results are obtained upon labeling of a Cys at position 54 or 58. Taken together, these results indicate that Asp-55 and Met-56 are located at or close to the ion-binding site while Ser-54, Ser-57, and Gly-58 may be close to the proline translocation pathway. In addition, the data prod at an involvement of the latter residues in ligand-induced conformational dynamics that are crucial for cation-coupled transport.

Inflammation seems to be associated with the presence of a specific clinical subtype in PD that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-β as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PD and predict progression.

We provide the first rational approach to the diagnosis of severe GHD in the newborn and evidence for gender dichotomy of the neonatal GH axis.

Naturally occurring autoantibodies (NAbs) against a number of potentially disease-associated cellular proteins, including Amyloid-beta1–42 (Abeta1–42), Alpha-synuclein (Asyn), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and S100 calcium binding protein B (S100B) have been suggested to be associated with neurodegenerative disorders, in particular Alzheimer’s (AD) and Parkinson’s disease (PD). Whereas the (reduced) occurrence of specific NAbs in AD is widely accepted, previous literature examining the relation of these NAb titres between PD patients and controls, as well as comparing these levels with demographic and clinical parameters in PD patients have produced inconsistent findings. We therefore aimed, in a cross-sectional approach, to determine serum titres of the above NAbs in a cohort of 93 PD patients (31 of them demented) and 194 controls. Levels were correlated with demographic and clinical variables, cerebrospinal fluid Abeta1–42, total tau and phospho-tau levels, as well as with single nucleotide polymorphisms (SNPs) of genes which either have been reported to influence the immune system, the amyloid cascade or the occurrence of PD (ApoE, GSK3B, HLA-DRA, HSPA5, SNCA, and STK39). The investigated NAb titres were neither significantly associated with the occurrence of PD, nor with demographic and clinical parameters, neurodegenerative markers or genetic variables. These results argue against a major potential of blood-borne parameters of the adaptive immune system to serve as trait or state markers in PD.