Introduction of Fluorine and Fluorine-Containing Functional Groups

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C[BOND]F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal—fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.Chemistry and Chemical Biolog

Design, Synthese und Evaluation selektiver Inhibitoren in Modellen der akuten myeloischen Leukämie sowie der Alzheimer Demenz

Die derzeitige Standardbehandlung der akuten myeloischen Leukämie (AML) mit einer Chemotherapie ist nicht nur sehr aggressiv sondern für die Mehrheit der Patienten auch ineffektiv. Zielgerichtete Therapieansätze sind daher äußerst erstrebenswert. Jüngst wurde die α-Isoform der Glykogen Synthase Kinase-3 (GSK-3) als mögliches Target der AML identifiziert. Der Hauptfokus dieser Dissertation lag in der Entwicklung, Synthese und Evaluation isoform-selektiver GSK-3-Inhibitoren. Der α-selektive GSK-3-Inhibitor BSc5090 war dabei nicht nur in vitro und in vivo aktiv, sondern zeigte auch eine vielversprechende Wirkung im Krankheitsmodell der AML. Die Inhibition der katalytischen β5-Untereinheit des 20S-Proteasoms ist ein anerkannter Ansatz für die Behandlung von hämatologischen Krebserkrankungen. Basierend auf dieser Thematik wurde mittels mechanistischer Studien untersucht, inwiefern die enzymatische Aktivität der ß5-Untereinheit von der Konformationsänderung von Met45 und dem Ligand abhängt. Ein weiteres Teilgebiet dieser Arbeit stellte die Entwicklung neuer Therapieansätze für die Alzheimer Demenz dar. Die GSK-3 und die humane Glutaminyl-Cyclase (hQC) stehen als mögliche Verursacher der Alzheimer Demenz stark im Fokus der Forschung. In einem dual-selektivem Ansatz konnten die GSK-3 und die hQC gleichzeitig inhibiert werden

Parasitic Cape honeybee workers, Apis mellifera capensis, evade policing

Relocation of the Cape honeybee, Apis mellifera capensis, by bee-keepers from southern to northern South Africa in 1990 has caused widespread death of managed African honeybee, A. m. scutellata, colonies. Apis mellifera capensis worker bees are able to lay diploid, female eggs without mating by means of automictic thelytoky (meiosis followed by fusion of two meiotic products to restore egg diploidy), whereas workers of other honeybee subspecies are able to lay only haploid, male eggs. The A. m. capensis workers, which are parasitizing and killing A. m. scutellata colonies in northern South Africa, are the asexual offspring of a single, original worker in which the small amount of genetic variation observed is due to crossing over during meiosis (P. Kryger, personal communication). Here we elucidate two principal mechanisms underlying this parasitism. Parasitic A. m. capensis workers activate their ovaries in host colonies that have a queen present (queenright colonies), and they lay eggs that evade being killed by other workers (worker policing)—the normal fate of worker-laid eggs in colonies with a queen. This unique parasitism by workers is an instance in which a society is unable to control the selfish actions of its members

Targeting a cancer-specific LYPD3 glycoform for tumor therapy

Introduction: One of the most drastic changes in cancer is the altered glycosylation of proteins and lipids, giving rise to truncated O-glycans like the Thomsen Friedenreich (TF) or Thomsen nouvelle (Tn) antigen, which are almost absent on normal cells. Combined protein-carbohydrate epitopes comprising these specific glycans are ideal candidates for potent targeted therapies given their excellent tumor specificity and broad cancer expression.Methods and results: We have generated GT-002, a monoclonal antibody specifically targeting the epithelial glycoprotein LYPD3 only in the presence of a TF glycosylation. It does not cross-react with non-glycosylated LYPD3 or TF on other glycoproteins in ELISA and flow cytometry. GT-002 binds to various tumor cell lines and stains tumor tissues of different cancer indications including squamous cell carcinoma of the head and neck. The remarkable tumor specificity was confirmed in an immunohistochemistry study on a normal human tissue panel including several LYPD3-positive organs, where GT-002 elicited almost completely abolished normal tissue binding. Consequently, we observed markedly reduced binding of GT-002 to normal human tissues compared to Lupartumab, a conventional anti-LYPD3 antibody previously in clinical development as antibody-drug conjugate (BAY1129980). Neuraminidase treatment of healthy tissues, resulting in cleavage of sialic acid residues, re-established binding of GT-002 comparable to Lupartumab, showing that the GT-002 epitope is masked by sialic acid in normal cells.Discussion: We believe that GT-002 is a promising candidate for development of antibody-drug- and radio-conjugates as well as bispecific molecules and chimeric antigen receptor therapeutics and highlights the powerful potential of antibodies against combined protein-carbohydrate epitopes to reduce on-target/off-tumor cytotoxicity

6-OHDA-induced dopaminergic neurodegeneration in <i>Caenorhabditis elegans</i> is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33

<div><p>Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson’s disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting <i>Caenorhabditis elegans</i> dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the <u>t</u>rans<u>t</u>hyretin-<u>r</u>elated gene <i>ttr-33</i>. The only described <i>C</i>. <i>elegans</i> transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of <i>C</i>. <i>elegans</i> larvae and is predicted to be a secreted protein. TTR-33 protects <i>C</i>. <i>elegans</i> from oxidative stress induced by paraquat or H₂O₂ at an organismal level. The increased oxidative stress sensitivity of <i>ttr-33</i> mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the <i>C</i>. <i>elegans</i> cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.</p></div

Premature Discontinuation of Pediatric Randomized Controlled Trials : A Retrospective Cohort Study

Objectives To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. Study design A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. Results We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). Conclusion Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.Peer reviewe

Characterizing Emerging Canine H3 Influenza Viruses.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements