Diffusion tensor imaging in frontostriatal tracts is associated with executive functioning in very preterm children at 9 years of age

Background Very preterm birth can disturb brain maturation and subject these high-risk children to neurocognitive difficulties later. Objective The aim of the study was to evaluate the impact of prematurity on microstructure of frontostriatal tracts in children with no severe neurologic impairment, and to study whether the diffusion tensor imaging metrics of frontostriatal tracts correlate to executive functioning. Materials and methods The prospective cohort study comprised 54 very preterm children (mean gestational age 28.8 weeks) and 20 age- and gender-matched term children. None of the children had severe neurologic impairment. The children underwent diffusion tensor imaging and neuropsychological assessments at a mean age of 9 years. We measured quantitative diffusion tensor imaging metrics of frontostriatal tracts using probabilistic tractography. We also administered five subtests from the Developmental Neuropsychological Assessment, Second Edition, to evaluate executive functioning. Results Very preterm children had significantly higher fractional anisotropy and axial diffusivity values (PPeer reviewe

Medium-Throughput Detection of Hsp90/Cdc37 Protein-Protein Interaction Inhibitors Using a Split Renilla Luciferase-Based Assay

The protein-folding chaperone Hsp90 enables the maturation and stability of various oncogenic signaling proteins and is thus pursued as a cancer drug target. Folding in particular of protein kinases is assisted by the co-chaperone Cdc37. Several inhibitors against the Hsp90 ATP-binding site have been developed. However, they displayed significant toxicity in clinical trials. By contrast, the natural product conglobatin A has an exceptionally low toxicity in mice. It targets the protein-protein interface (PPI) of Hsp90 and Cdc37, suggesting that interface inhibitors have an interesting drug development potential. In order to identify inhibitors of the Hsp90/Cdc37 PPI, we have established a mammalian cell lysate-based, medium-throughput amenable split Renilla luciferase assay. This assay employs N-terminal and C-terminal fragments of Renilla luciferase fused to full-length human Hsp90 and Cdc37, respectively. We expect that our assay will allow for the identification of novel Hsp90/Cdc37 interaction inhibitors. Such tool compounds will help to evaluate whether the toxicity profile of Hsp90/Cdc37 PPI inhibitors is in general more favorable than that of ATP-competitive Hsp90 inhibitors. Further development of such tool compounds may lead to new classes of Hsp90 inhibitors with applications in cancer and other diseases

Diffusion tensor imaging in frontostriatal tracts is associated with executive functioning in very preterm children at 9 years of age

Background Very preterm birth can disturb brain maturation and subject these high-risk children to neurocognitive difficulties later. Objective The aim of the study was to evaluate the impact of prematurity on microstructure of frontostriatal tracts in children with no severe neurologic impairment, and to study whether the diffusion tensor imaging metrics of frontostriatal tracts correlate to executive functioning. Materials and methods The prospective cohort study comprised 54 very preterm children (mean gestational age 28.8 weeks) and 20 age- and gender-matched term children. None of the children had severe neurologic impairment. The children underwent diffusion tensor imaging and neuropsychological assessments at a mean age of 9 years. We measured quantitative diffusion tensor imaging metrics of frontostriatal tracts using probabilistic tractography. We also administered five subtests from the Developmental Neuropsychological Assessment, Second Edition, to evaluate executive functioning. Results Very preterm children had significantly higher fractional anisotropy and axial diffusivity values (PConclusion Prematurity has a long-term effect on frontostriatal white matter microstructure that might contribute to difficulties in executive functioning.</div

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM–44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM–44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases

Contrasting microbiotas between Finnish and Estonian infants : exposure to Acinetobacter may contribute to the allergy gap

Background Allergic diseases are more common in Finland than in Estonia, which-according to the biodiversity hypothesis-could relate to differences in early microbial exposures. Methods We aimed at defining possible microbial perturbations preceding early atopic sensitization. Stool, nasal and skin samples of 6-month-old DIABIMMUNE study participants with HLA susceptibility to type 1 diabetes were collected. We compared microbiotas of sensitized (determined by specific IgE results at 18 months of age) and unsensitized Estonian and Finnish children. Results Sensitization was differentially targeted between populations, as egg-specific and birch pollen-specific IgE was more common in Finland. Microbial diversity and community composition also differed; the genusAcinetobacterwas more abundant in Estonian skin and nasal samples. Particularly, the strain-level profile ofAcinetobacter lwoffiiwas more diverse in Estonian samples. Early microbiota was not generally associated with later sensitization. Microbial composition tended to differ between children with or without IgE-related sensitization, but only in Finland. While land-use pattern (ie green areas vs. urban landscapes around the children's homes) was not associated with microbiota as a whole, it associated with the composition of the genusAcinetobacter. Breastfeeding affected gut microbial composition and seemed to protect from sensitization. Conclusions In accordance with the biodiversity hypothesis, our results support disparate early exposure to environmental microbes between Finnish and Estonian children and suggest a significant role of the genusAcinetobacterin the allergy gap between the two populations. The significance of the observed differences for later allergic sensitization remains open.Peer reviewe

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

Simple SummaryThe correct folding of proteins is essential for their activity. Therefore, cells have evolved protein-folding chaperones, such as Hsp90. Interestingly, in several cancer cells, Hsp90 appears to have a role that is more important than normal. The current working model suggests that, with the help of its co-chaperone, Cdc37, it stabilizes mutant kinases. However, Hsp90, together with Cdc37, assists additional proteins that may be relevant in cancer. We demonstrate that the Hsp90-dependent stability of the transcription factor HIF-1 alpha and one of its downstream transcriptional targets, galectin-3, is important to maintain the elevated activity of the major oncogene KRAS. This is because galectin-3 stabilizes the MAPK-signaling complexes of K-Ras, which is called a nanocluster. In addition, we identified six drug-like small molecules that inhibit the Hsp90/Cdc37 protein interface at low micro molar concentrations. Given the co-occurrence of mutant KRAS with high HIF-1 alpha and high galectin-3 levels in pancreatic cancer, our results suggest an application of Hsp90 inhibitors in this cancer type.The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1 alpha. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1 alpha-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 mu M-44 mu M in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases

Diffusion tensor imaging is associated with motor outcomes of very preterm born children at 11 years of age

Aim Very preterm children born Methods A cohort of 37 very preterm infants (mean gestational age 29 4/7, SD 2 0/7) born in 2004-2006 in Turku University Hospital underwent diffusion tensor imaging at term. A region of interest analysis of fractional anisotropy and mean diffusivity was performed. Motor outcomes at 11 years of age were measured with the Movement Assessment Battery for Children - Second Edition. Results The diffusion metrics of the corpus callosum (genu P = .005, splenium P = .049), the left corona radiata (P = .035) and the right optic radiation (P = .017) were related to later motor performance. Mean diffusivity decreased and fractional anisotropy increased in proportion to the improving performance. Conclusion The diffusion metrics of the genu and splenium of the corpus callosum, the left corona radiata and the right optic radiation at term were associated with motor skills at 11 years of age. Diffusion tensor imaging should be further studied as a potential tool in recognising children at risk for motor impairment.</div

Hyaluronic acid-coated gold nanoparticles as an anticancer drug delivery system - Biological characterization and efficacy

[cat] Els actuals tractaments oncòlogics presentan una eficàcia limitada que forcen la recerca de noves teràpies mes eficients. En aquest sentit, la nanotecnologia ha generat moltes expectatives. Durant aquesta tesi, hem desenvolupat un sistema d’alliberaciò de fârmacs formats per nanopartícules d’or (AuNP) recobertes amb àcid hialurònic (HA), dirigit a CD44, una glicoproteïna que es sobreexpresa a la superfície cel.lular de diferents tipus de tumor. Aquest sistema (EDS: Endor Delivery System) proporciona una plataforma per a la conjugaciò de diferents fârmacs antitumorals per tal de tractar el câncer d’una manera més eficient. Aquesta tesi demostra que les propietats úniques que aporten les AuNP es mantenen quan la molqcula que dirigeix al tumor (HA) i l’agent antitumoral sòn conjugats. El recobriment d’HA estabilitza les AuNP, millorant la seva biocompatibilitat. A mps, tambp es demostra que l’EDS va dirigit a CD44, al qual s’uneix i ps internalitzat a les cèl.lules. El nanotransportador no presenta efectes tòxics ni in vitro ni in vivo. Quan el nanotransportador s’uneix a un agent antitumoral (Cisplatí, CIS), es va alliberant de manera gradual en medis fisiològics, a travps de l’acciò de les hialuronidases i del canvi de pH, alliberant el fârmac amb la seva forma activa. L’eficâcia in vivo del CIS conjugat a l’EDS ha mostrat ser superior a la del fârmac lliure. No obstant aixó, sòn necessaris més estudis de seguretat y toxicitat. Nous fàrmacs antitumorals estan sent estudiats per tal de validar l’EDS com una plataforma per a l’alliberaciò de fârmacs antitumorals.[eng] Novel stategies are needed to improve the limited efficacy of current cancer therapies. High expectations are directed towards nanotechnology-based applications in cancer medicine. We have developed a drug delivery system based on hyaluronic acid (HA) ­coated gold nanoparticles (AuNPs) that targets CD44, a cell surface glycoprotein overexpressed by various cancer cells. This nanocarrier (EDS: Endor Drug Delivery System) provides a platform for the conjugation of anticancer agents for a more efficient cancer treatment. We show that the unique characteristics of AuNPs remain unchanged when the targeting ligand and a chemotherapeutic agent are conjugated. HA-coating stabilizes AuNPs and improves their biocompatibility. EDS is shown to target CD44 and is internalized through this receptor. The nanocarrier does not cause toxic effects in vitro or in vivo. After conjugating an anticancer agent (CIS: cisplatin) to the nanocarrier, EDS shows gradual drug release in physiological media due to changes in pH and hyaluronidase activity, and the drug reaches its target cells in its active form. In vivo efficacy of EDS­CIS conjugate is higher than that of free cisplatin. However, more safety and toxicological studies must be conducted. New drug candidates are being tested in order to validate EDS as a platform for antitumoral drugs