Corrosion of reinforcement in reinforced concrete is a huge problem. Corrosion of reinforcement has a great effect on the service life of reinforced concrete structures. The subject of this work is to verify the inhibitors properties and their efficiency using physical and electrochemical methods. The aim of this work is the design of formwork panels with corrosion protection. The formwork panels are on different material basis. Corrosion protection is ensured by the use of migration corrosion inhibitors.

Background: The value of liver-directed therapy (LDT) in patients with metastasic renal cell carcinoma (MRCC) is still an active field of research, particularly in the era of tyrosinkinase inhibitor (TKI) therapy. Methods: The records of 35 patients with MRCC undergoing LDT of metastasic liver lesions between 1992 and 2015 were retrospectively analyzed. Immediate postoperative TKI was given in a subgroup of patients after LDT for metastasic lesions. Uni- and multivariate models were applied to assess overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS). Results: Following primary tumor (renal cell cancer) resection and LDT, respectively, median OS was better for a total of 16 patients (41 %) receiving immediate postoperative TKI with 151 and 98 months, when compared to patients without TKI therapy with 61 (p = 0.003) and 40 months (p = 0.032). Immediate postoperative TKI was associated with better median PFS (47 months versus 19 months; p = 0.023), whereas in DFS only a trend was observed (51 months versus 19 months; p = 0.110). Conclusions: LDT should be considered as a suitable additive tool in the era of TKI therapy of MRCC to the liver. In this context, postoperative TKI therapy seems to be associated with better OS and PFS, but not DFS.

1 AbstractAbstractAbstractAbstract Proteins secreted in the male reproductive tract play a key role in post-testicular development of sperm and in further steps needed for fertilization. Sperm maturation represents a key step in the reproduction process. Sperm, during the passage through the epididymis undergoes significant changes due to proteolytic and glycolytic activities in the epididymal fluid. Inhibitor of acrosin protects spermatozoa and reproductive epithelium against proteolytic degradation and also protects binding sites for ZP on sperm plasma membrane. In boar reproductive system acrosin inhibitor (AI) was found in seminal plasma and on sperm plasma membrane. Polyclonal antibody recognized AI in extracts of the cauda epididymidis, seminal vesicles, prostate, and Cowper's glands. Using immunofluorescence method has revealed the AI in the epithelium and lumen of these organs but also on the surface of epididymal and ejaculated spermatozoa. We registered the increasing signal of AI from caput to cauda epididymis. Gene expression of AI mRNA was detected in the epididymis, seminal vesicles, prostate, and Cowper's glands and increased gradually throughout the epididymal duct. In present study, we also monitored AI in boar epididymal fluid and spermatozoa along the organ. In the epididymis, AI may...

The dissemination of tumor cells to distant organs i.e. metastasis is an exceedingly complex process leading to 90% of all cancer deaths. Despite being so clinically important, little is known about this process that requires tumor cells to leave the primary tumor site, intravasate and transport through the blood stream, extravasate and colonize at secondary sites leading to distant metastases. Survivin, a member of the IAP (Inhibitor of Apoptosis) family with known functions in apoptosis and mitosis, is highly expressed in aggressive tumors and is associated with poor prognosis and adverse clinical outcome. But the mechanistic role of survivin in metastatic dissemination has not been investigated. In this study, we demonstrate an important and novel role of survivin in activating a broad gene expression program in tumor cells. Of particular importance is the upregulation of a distinct class of cell adhesion molecules, particularly fibronectin. This IAP mediated gene regulation requires synergistic intermolecular cooperation between survivin and its related cofactor molecule, XIAP that results in activation of NF-κB dependent fibronectin gene expression. The binding of fibronectin with its cognate cell surface receptors initiates outside–in signaling leading to the autocrine and paracrine activation of cell motility kinases, FAK and Src, in turn leading to enhanced tumor invasion and metastasis. The importance of survivin and XIAP in the process of metastasis has also been demonstrated in vivousing intrasplenic injections in mouse models. Overall this study is the first to place survivin upstream of transcriptional activation of gene expression particularly fibronectin. In addition, it also demonstrates the importance of survivin-XIAP complex in mediating NF-κB activation which in turn switches on the expression of various target genes involved in tumor metastasis. Hence this study dissects the upstream and downstream requirements of survivin- XIAP complex mediated tumor dissemination and metastasis. Significance of this Study The hallmark of end-stage cancer is metastasis, an incurable condition almost invariably associated with death from disease. Despite a better understanding of the metastatic process, and the identification of key gene expression requirements of this pathway, the development of anti-metastatic therapies has lagged behind, with no viable options being currently offered in the clinical setting. Our findings that Inhibitor of Apoptosis (IAP) proteins functions as metastasis-promoting genes independently of cell survival, but through activation of cell motility could have important ramifications for the broader application of IAP antagonists currently in early clinical trials, as novel anti-metastatic therapies.

Au sein du laboratoire, par une stratégie de conception de médicaments par la méthode des fragments, nous avons généré une nouvelle famille d'inhibiteurs de cyclophilines, les SMCypI (« Small-Molecule Cyclophilin Inhibitors »), non liée aux autres inhibiteurs de cyclophilines existants. Les cyclophilines sont des protéines cellulaires impliquées dans un grand nombre de processus biologiques. Toutefois, les inhibiteurs de cyclophilines disponibles possèdent de nombreux inconvénients qui rendent leur utilisation clinique difficile. Au cours de ma thèse nous nous sommes intéressés au développement des SMCypI dans deux domaines en particulier, la Virologie et l’Hépatologie.Dans le domaine de la Virologie, les cyclophilines sont impliquées dans la réplication de plusieurs virus et constituent donc une cible de choix dans le développement d'antiviraux à large spectre. Dans un premier temps, nous nous sommes intéressés à la caractérisation de l’activité antivirale de ces molécules sur le virus de l’Hépatite C, avec comme objectif de démontrer leur activité pangénotypique, leur haute barrière à la résistance, leur mécanisme d’action et leur activité antivirale à large spectre pour d’autres virus de la famille des Flaviviridae.Dans le domaine de l’Hépatologie, les lésions d’ischémie-reperfusion hépatique sont rencontrés pendant la chirurgie hépatique et la transplantation hépatique. La mitochondrie est un acteur majeur via l’ouverture du pore de transition de perméabilité mitochondrial. L’ouverture du pore est modulée par la cyclophiline D. Dans un deuxième temps, nous avons étudié les effets des SMCypI sur cette deuxième cible. Cela nous a permis de démontrer leur effet hépatoprotecteur dans un modèle murin d’ischémie-reperfusion hépatique.L’ensemble de ces résultats ouvre la porte pour le concept des antiviraux à large spectre, et l’utilité dans le domaine de l’hépatologie comme molécules hépatoprotectrices.... / In our laboratory we previously reported a rational design of a new family of smallmolecule cyclophilins inhibitors, SMCypI, unrelated to other cyclophilins inhibitors by means of a complex fragment-based drug discovery approach. Cyclophilins are cellular proteins involved in multiple biological processes. Unfortunately, different disadvantages have limited their clinical development. The aim my thesis was to study the SMCypI in two particulars fields, Virology and Hepatology.In the field of Virology, cyclophilins inhibitors are involved in viral replication of multiple viruses, which make them a convenient target for the development of “broad-spectrum antivirals”. Here, we first characterized the pangenotypic anti-HCV activity of this new family of SMCypI, with high resistance barrier. We studied its mechanism of action andits broad antiviral activity on other members of the Flaviviridae family.In the field of Hepatology, ischemia-reperfusion injuries occur during liver surgery and liver transplantation. Mitochondria play a central role in the opening of mitochondrial permeability transition pore. The opening of this pore is mainly regulated by cyclophilin D. The aim of the second part of our work was to demonstrated a hepatoprotective effect of the SMCypl in a murine model of hepatic ischemia reperfusion injury.Overall, these results are leading the way to the development of broad-spectrumantiviral drugs and their use in hepatology as hepatoprotective drugs....

This thesis aims to review if there is an association between antidepressants and caries in children and adolescents. Previous established evidence exhibits that adults prescribed tricyclic antidepressants have an increased risk of caries. Simultaneously, a global trend of increased prescriptions of antidepressant medications is seen. In Sweden during 2018, 0–17-year old’s on antidepressant medication represented 1,6% percent of the total population. It is of utmost relevance to investigate the association between antidepressants and caries as the increasing population of medicating children may lead to an increased caries prevalence. A systematic literature review was performed in accordance with PRISMAs guidelines. The title-abstract and keywords searches were conducted in the following seven bibliographic databases: PubMed, EMBASE, CINAHL, Scopus, Web of Science, PsycINFO and MedLine. The search consisted of blocks based on “caries”, “children” and “antidepressants”. Unique articles were reviewed from title and abstract. Articles that met the criteria were reviewed in full text. The search generated 1829 unique articles, 1891 were excluded from the predefined criteria. 10 articles were reviewed in full text. None of the articles were eligible within the criteria of inclusion. The conclusion is that further research is needed in this area to assess the possible association between antidepressants and caries in children and adolescents. / Uppsatsen syftar till att sammanställa forskningsläget för sambandet mellan antidepressiv medicinering och karies hos barn och ungdomar. Tidigare evidens visar att vuxna som medicinerar med tricykliska antidepressiva har ökad kariesrisk. Samtidigt kan man globalt se en generell förskrivningsökning av antidepressiva. I Sverige under 2018, utgjorde användarna av antidepressiva i åldersgruppen 0–17 år 1,6% av totalpopulationen. Det är av högsta relevans att undersöka om det finns en potentiell association mellan antidepressiva och karies finns då den ökande populationen av medicinerande barn kan medföra ökad kariesprevalens. En systematisk litteraturöversikt genomfördes enligt PRISMAs riktlinjer. Titel- sammanfattnings och nyckelordssökningen utnyttjade följande sju elektroniska databaser: PubMed, EMBASE, CINAHL, Scopus, Web of Science, PsycINFO och MedLine. Sökningen utfördes i block utifrån “karies”, “barn” och “antidepressiva”. Unika artiklar granskades utifrån titel och abstrakt. Artiklar som uppfyllde förutbestämda kriterier för inklusion granskades i fulltext. Utifrån sökningen påträffades 1829 unika artiklar, varav 1819 exkluderades utifrån från titel och abstrakt. 10 artiklar granskades i fulltext och vi konstaterade att ingen artikel uppfyllde kriterierierna. Slutsatsen för studien är att fler studier och mer forskning behövs inom området. Detta för att kunna svara på om det finns ett samband mellan antidepressiva och karies hos barn.

Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

No description available.

DNA is wrapped around proteins called histones, whose modification regulates numerous cellular processes. Therefore it is not surprising that mutations in the genes that modify the histones are frequently associated with human cancer. For example, mutations in SETD2, encoding the sole enzyme that catalyses histone H3 lysine 36 trimethylation (H3K36me3), occur frequently in multiple cancer types. This identifies H3K36me3 loss as an important event in cancer development, and also as a potential therapeutic target. This thesis investigates the following questions: (1) how does the loss of H3K36me3 contribute to cancer development; and (2) what therapy can be used to kill cancers that have already lost H3K36me3. To answer the first question, this thesis shows that H3K36me3 facilitates the accurate repair of DNA double-stranded breaks (DSBs) by homologous recombination (HR). H3K36me3 promotes HR by recruiting CtIP to the site of DSBs to carry out resection, allowing the binding of HR proteins (such as RPA and RAD51) to the damage sites. Thus it is proposed that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions suppresses genetic mutations which could promote tumourigenesis. To answer the second question, this thesis reveals a clinically relevant synthetic lethal interaction between H3K36me3 loss and WEE1 inhibition. WEE1 inhibition selectively kills H3K36me3-deficient cells by inhibiting DNA replication, and subsequent fork stalling results in MUS81 endonuclease-dependent DNA damage and cell death. The mechanism is found to be synergistic depletion of RRM2 (ribonucleotide reductase small subunit), the enzyme that generates deoxyribonucleotides (dNTPs). This work reveals two pathways that regulate RRM2: one involves transcriptional activation of RRM2 by H3K36me3, and the other involves RRM2 degradation regulated by Cyclin-Dependent Kinase, CDK1 (which is controlled by WEE1, CHK1 and ATR). Based on this mechanism, the synthetic lethal interaction is expanded, from between two genes, to between two pathways. Supported by in vivo experiments, the study suggests that patients with cancers that have lost H3K36me3 could benefit from treatment with the inhibitors of WEE1, CHK1 or ATR.

<p>Despite advancements in therapies, such as surgery, irradiation (IR) and chemotherapy, outcome for patients suffering from glioblastoma (GBM) remains fatal; the median survival time is only about 15 months. Even with novel therapeutic targets, networks and signaling pathways being discovered, monotherapy with such agents targeting such pathways has been disappointing in clinical trials. Poor prognosis for GBM can be attributed to several factors, including failure of drugs to cross the blood-brain-barrier (BBB), tumor heterogeneity, invasiveness, and angiogenesis. Development of tumor resistance, particularly to temozolomide (TMZ) and IR, creates a substantial clinical challenge.</p><p> </p><p>The primary focus of the work described herein was to develop a modeling and simulation approach that could be applied to rationally develop novel combination therapies and dose regimens that mitigate resistance development. Specifically, TMZ was combined with small molecule inhibitors that are either currently in clinical trials or are approved drugs for other cancer types, and which target the disease at various resistance signaling pathways that are induced in response to TMZ monotherapy. To accomplish this objective, an integrated PKPD modeling approach was used. A PK model for each drug was first defined. PK models were subsequently linked to a PD model description of tumor growth dynamics in the presence of a single drug or combinations of drugs. A key outcome of these combined PKPD models was tumor static concentration (TSC) curves of TMZ in combination with small molecule inhibitors that identify combination drug exposures predicted to arrest tumor growth. This approach was applied to TMZ in combination with abemaciclib (a dual CDK4/6 small molecule inhibitor) based on data from a published study evaluating abemaciclib (ACB) efficacy in combination with TMZ in a U87 GBM xenograft model. TSC was also constructed for TMZ in combination with RG7388 (MDM2 inhibitor) based on the data from an in-vivo study that evaluated effects on tumor growth suppression of these small molecule inhibitors in combination with TMZ in GBM 10 patient derived xenografts.</p><p>In GBM 43 mouse xenografts, emergence of resistance to TMZ treatment was identified. Thus, a resistance integrated PKPD model was developed to predict tumor growth kinetics after treatment with TMZ in GBM 43 tumors. Population PK models in immune deficient NOD.Cg-<em>Prkdc^scid Il2rg^tm1Wjl</em>/SzJ (NSG) mice for TMZ and small molecule inhibitors (GDC0068/RG7112) were developed based on a combination of data obtained from an in-vivo study and published sources. Subsequently, PK models were linked to tumor volume data obtained from GBM 43 subcutaneous xenografts. Model parameters quantifying tumor volume dynamics were precisely estimated (coefficient of variation < 40%) compared to a base tumor growth inhibition model in GBM 43 that did not incorporate resistance development. Graphical diagnostics of the resistance incorporated PKPD tumor growth inhibition model demonstrated a superior fit compared to the base model, and accurately captured the emergence of resistance to the TMZ monotherapy treatment observed in the GBM 43 patient derived xenograft model.</p>