Studies on Matrix Metalloproteinase (MMP-2, -9 and -14) and β2 Integrin Targeting as Potential Anticancer Therapeutics

Proteolytic enzymes, such as matrix metalloproteinases (MMP), are associated to the progression of several cancers. They degrade extracellular components, which helps tumors to expand and cancer cells to escape from the primary site. Of all MMPs, gelatinases (MMP-2 and -9) and membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14), in particular, are often associated to more aggressive types of head and neck carcinomas as well as to a poorer outcome in patient survival. Although therapies during the last decades have advanced, the mortality of the disease is still rather high and adjuvant therapies are searched for continuously. MMP-9 and MT1-MMP are also involved in neo-angiogenesis, which is necessary for tumor expansion. For this reason, we have identified synthetic peptides-targeting gelatinases and MT1-MMP, and have also evaluated their anticancer effects in vitro and in vivo. Antigelatinolytic peptides effectively inhibited tongue-carcinoma cell invasion and reduced the growth of xenografted tumors. In tumor samples of mice that were treated with antigelatinolytic peptides, the micro-vessel density was significantly reduced. We also identified a novel MT1-MMP targeting peptide and demonstrated that it exerted anticancer effects against several malignant cell lines in vitro. The effects of MT1-MMP inhibition on tongue-squamous cell carcinomas were evaluated by using xenograft tumors, which it effectively inhibited. Tranexamic acid was also demonstrated to inhibit tongue-squamous cell carcinoma invasion, most probably due to its ability to prevent the plasmin-mediated activation of proMMP-9. Leukocyte β2 integrins are another interesting option when evaluating targets for the therapeutic intervention of inflammatory conditions or malignancies of hematopoietic origin, since β2 integrins are expressed mainly by leukocytes. We identified a novel technique for screening small-molecule libraries against β2 integrins, and by using this technique we identified a novel αMβ2 integrin-binding chemical (IMB-10). IMB-10 significantly enhances leukocyte adhesion and inhibits their motility. We also demonstrated that IMB-10 can be used to inhibit inflammation and lymphoma growth in vivo. Interestingly, IMB-10 also reduced leukocyte tumor infiltration and inhibited tumor invasion.

Aspects of tautomerism 9-solvolysis of normal and pseudo phthaloyl chlorides

Solvolysis of normal and pseudo phthaloyl chlorides in aqueous acetone and in aqueous dioxane has revealed that the former solvolyses about hundred-fold faster than the latter. Contrary to the accepted belief, there is no evidence for equilibrium between the normal and the pseudo forms of phthaloyl chloride, under a variety of conditions.

Growth differentiation factor 9 signalling in the ovary

In the ovary, two new members of the large TGF-beta superfamily of growth factors were discovered in the 1990s. The oocyte was shown to express two closely related growth factors that were named growth differentiation factor 9 (GDF-9) and growth differentiation factor 9B (GDF-9B). Both of these proteins are required for normal ovarian follicle development although their individual significance varies between species. GDF-9 and GDF-9B mRNAs are expressed in the human oocytes from the primary follicle stage onwards. This thesis project was aimed to define the signalling mechanisms utilized by the oocyte secreted GDF-9. We used primary cultures of human granulosa luteal cells (hGL) as our cell model, and recombinant adenovirus-mediated gene transfer in manipulating the TGF-b family signalling cascade molecules in these cells. Overexpression of the constitutively active forms of the seven type I receptors, the activin receptor-like kinases 1-7 (ALK1-7), using recombinant adenoviruses caused a specific activation of either the Smad1 or Smad2 pathway proteins depending on the ALK used. Activation of both Smad1 and Smad2 proteins also stimulated the expression of dimeric inhibin B protein in hGL cells. Treatment with recombinant GDF-9 protein induced the specific activation of the Smad2 pathway and stimulated the expression of inhibin betaB subunit mRNA as well as inhibin B protein secretion in our cell model. Recombinant GDF-9 also activated the Smad3-responsive CAGA-luciferase reported construct, and the GDF-9 response in hGL cells was markedly potentiated upon the overexpression of Alk5 by adenoviral gene transduction. Alk5 overexpression also enhanced the GDF-9 induced inhibin B secretion by these cells. Similarly, in a mouse teratocarcinoma cell line P19, GDF-9 could activate the Smad2/3 pathway, and overexpression of ALK5 in COS7 cells rendered them responsive to GDF-9. Furthermore, transfection of rat granulosa cells with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 effects. In conclusion, this thesis shows that both Smad1 and Smad2 pathways are involved in controlling the regulation of inhibin B secretion. Therefore, in addition to endocrine control of inhibin production by the pituitary gonadotropins, also local paracrine factors within in the ovary, like the oocyte-derived growth factors, may contribute to controlling inhibin secretion. This thesis shows as well that like other TGF-beta family ligands, also GDF-9 signalling is mediated by the canonical type I and type II receptors with serine/threonine kinase activity, and the intracellular transcription factors, the Smads. Although GDF-9 binds to the BMP type II receptor, its downstream actions are specifically mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins.

Tombstone of Marianne Benjamin nee Sussmann; Strangriede Cemetery (R 83.9); Hannover Cemeteries Tombs

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Tombstones of Joseph Benjamin and Marianne Benjamin nee Sussmann; Strangriede Cemetery (R 83.8 and R 83.9); Hannover Cemeteries Tombs

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Sitting-time and 9-year all-cause mortality in older women

Background Studies of mid-aged adults provide evidence of a relationship between sitting-time and all-cause mortality, but evidence in older adults is limited. The aim is to examine the relationship between total sitting-time and all-cause mortality in older women. Methods The prospective cohort design involved 6656 participants in the Australian Longitudinal Study on Women's Health who were followed for up to 9 years (2002, age 76–81, to 2011, age 85–90). Self-reported total sitting-time was linked to all-cause mortality data from the National Death Index from 2002 to 2011. Cox proportional hazard models were used to examine the relationship between sitting-time and all-cause mortality, with adjustment for potential sociodemographic, behavioural and health confounders. Results There were 2003 (30.1%) deaths during a median follow-up of 6 years. Compared with participants who sat <4 h/day, those who sat 8–11 h/day had a 1.45 times higher risk of death and those who sat ≥11 h/day had a 1.65 times higher risk of death. These risks remained after adding sociodemographic and behavioural covariates, but were attenuated after adjustment for health covariates. A significant interaction (p=0.02) was found between sitting-time and physical activity (PA), with increased mortality risk for prolonged sitting only among participants not meeting PA guidelines (HR for sitting ≥8 h/day: 1.31, 95% CI 1.07 to 1.61); HR for sitting ≥11 h/day: 1.47, CI 1.15 to 1.93). Conclusions Prolonged sitting-time was positively associated with all-cause mortality. Women who reported sitting for more than 8 h/day and did not meet PA guidelines had an increased risk of dying within the next 9 years.

Hermann Falck's Erdenweg und tragisches Ende 9. April 1943 1917-1943

Biography of Hermann Falck and story of his execution; contains copies of various letters.

Sleep and self-regulation from birth to 7 years: A retrospective study of children with and without ADHD at 8-9 years

Objective To examine mean level differences, and longitudinal and reciprocal relations among behavioral sleep problems, emotional dysregulation, and attentional regulation across early childhood for children with and without ADHD at 8-9 years. Method This study used data from Growing Up in Australia: The Longitudinal Study of Australian Children (LSAC) – Infant Cohort (n = 4109 analyzed). Children with and without ADHD were identified at age 8-9 years via parent-report of ADHD diagnosis and the 5-item Inattention-Hyperactivity subscale from the Strengths and Difficulties Questionnaire. Maternal report of child sleep problems and self-regulation was collected at 0-1, 2-3, 4-5 and 6-7 years of age. ANOVA was used to compare mean level differences in sleep problems, emotional and attentional regulation by ADHD group. Longitudinal structural equation modeling examined the relations among sleep and self-regulation across time in children with and without ADHD. Results Children with ADHD had persistently elevated levels of sleep problems (from infancy) and emotional and attentional dysregulation compared to controls (from 2-3 years of age). Sleep problems, emotional dysregulation, and attentional regulation were stable over time for both groups. Sleep problems were associated with greater emotional dysregulation two years later from 2-3 years of age for both groups, which in turn was associated with poorer attentional regulation. There was no direct relationship between sleep problems and later attentional regulation. Conclusion Sleep problems in children with and without ADHD are associated with emotional dysregulation, which in turn contributes to poorer attentional functioning. This study highlights the importance of assessing and managing sleep problems in young children.

Plan uchastkov nn 4, 7, 7a i 9 Chongarskogo poluostrova Henicheskogo raiona

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Vykopirovka plana Melitopol'skogo okruga Genicheskovo raiona poluostrova Chongar otgranichennogo v poriadke ustroistva Kolfonda s obrazovaniem posëlkov i rozbivkoiu na polia sevooborota goni, sogliasno plana zemleustraitelnykh rabot po 1925-1926 gg.; plan sostavlen 9 partiei po ustroistvu kolfonda

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Vykopirovka iz obshchego plana Biiuk-Onlarskoi dachi razverstaniia na uchastki KOMZET-a pod nazv. Biiuk-Onlarskii fond i Nom 9/10/24

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Vykopirovka s plana na zemelʻnyĭ otvod dli︠a︡ Evreĭskogo pereselenskogo uchastka N 9

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Ni(II)chelates of 4,9-dimethyl-5,8-dizadodeca-4,8-diene-2,11-dione-3,10-diphenyl hydrazone and related molecules

Syntheses and structural characterization of Ni(II) chelates of a new series of symmetric and unsymmetric tetradentate linear ligands are described. Preparative routes involve either the direct reaction between a metal complex and arene diazonium diazonium salts or a simple metal incorporation into the independently synthesized ligands. Recent X-ray structure determination of 4,9-dimethyl-5,8-diazadodeca-4,8-diene-2,11-dione-3,10-di(4′-methyl phenyl) hydrazonatonickel(II) complex reveals the geometry around the Ni(II) to be very close to square planar. The expected distortion because of the disposition of bulky aromatic groups on the neighbouring nitrogens is minimized by their projection in the opposite directions from the plane. PMP, IR and electronic spectral data for the complexes are quite in agreement with this structure.

Khersonskye fondy Uchastky N 1-9 i N 17-19

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Plan zemelʻnogo uchastka poselka Mendelʻsdorf N 9

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