FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen.

A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression.

Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615.

Design and synthesis of bioactive adamantanaminoalcohols and adamantanamines.

Adamantanamines 16, 18, 21, 24, 27, 28, 30, 32, 35, 36, 37, 40, 46 and 48 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. The effect of introducing a hydroxyl group close to the amino group on this class of compounds was examined for the first time.

Fine scale mapping of the breast cancer 16q12 locus.

Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5' end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants.

New oxapolycyclic cage amines with NMDA receptor antagonist and trypanocidal activities.

The synthesis of several (1,2,3,5,6,7-hexahydro-1,5:3,7-dimethano-4-benzoxonin-3-yl)amines and related compounds is reported. Several of them display very similar activity to memantine as NMDA receptor antagonists. Several derivatives showed a significant level of trypanocidal activity.

Design and synthesis of Trypanosoma brucei active 1-alkyloxy and 1-benzyloxyadamantano 2-guanylhydrazones.

Treating African trypanosomiasis: The synthesis and biological evaluation of novel 1-alkyloxy and 1-benzyloxyadamantano 2-guanylhydrazones, their 1-dioxa congeners and two 1-benzyladamantano 2-guanylhydrazones is reported. Preliminary structure-activity relationship data were elucidated and lead compounds suitable for further optimization were discovered.

Synthesis and pharmacological evaluation of (2-oxaadamant-1-yl)amines.

The synthesis of several (2-oxaadamant-1-yl)amines is reported. They were evaluated as NMDA receptor antagonists and several of them were more active than amantadine, but none was more potent than memantine. None of the tested compounds displayed antiviral activity.

Synthesis and pharmacological evaluation of several ring-contracted amantadine analogs.

The synthesis of several (3-noradamantyl)amines, [(3-noradamantyl)methyl]amines, (3,7-dimethyl-1-bisnoradamantyl)amines, and [(3,7-dimethyl-1-bisnoradamantyl)methyl]amines is reported. They were evaluated against a wide range of viruses and one of them inhibited the cytopathicity of influenza A virus at a concentration similar to that of amantadine. Several of the new polycyclic amines show an interesting activity as NMDA receptor antagonists.

Design and synthesis of bioactive 1,2-annulated adamantane derivatives.

Adamantanopyrrolidines 8, 9 and 10, adamantanopyrrolidines 16 and 18, adamantanoxazolone 20, adamantanopyrazolone 23, adamantanopyrazolothione 24 and adamantanocyclopentanamine 32 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. Pyrrolidine 16 proved to be the most active of the compounds tested against influenza A virus, being 4-fold more active than amantadine, equipotent to rimantadine and 19-fold more potent than ribavirin.

Design, synthesis, and trypanocidal activity of new aminoadamantane derivatives.

To develop functionalized adamantanes for treating African trypanosomiasis, we report on the synthesis of new 1-alkyl-2-aminoadamantanes 1a- i, 1-alkyltricyclo[3.3.1.

Functional characterisation of the iron superoxide dismutase gene repertoire in Trypanosoma brucei.

Superoxide dismutases (SOD) are a family of antioxidant enzymes that function by removing superoxide anions from the cellular environment. Here, we show that the African trypanosome, Trypanosoma brucei, expresses four SOD isoforms, three of which we have validated biochemically as iron dependent, a feature normally associated with prokaryotic SODs. Localisation studies reveal that two of the enzymes are found predominantly in a parasite-specific organelle, the glycosome (TbSODB1 and TbSODB2), while the other two are targeted to the mitochondrion (TbSODA and TbSODC).

Vitamin C biosynthesis in trypanosomes: a role for the glycosome.

The capacity to synthesize vitamin C (ascorbate) is widespread in eukaryotes but is absent from humans. The last step in the biosynthetic pathway involves the conversion of an aldonolactone substrate to ascorbate, a reaction catalyzed by members of an FAD-dependent family of oxidoreductases. Here we demonstrate that both the African trypanosome, Trypanosoma brucei, and the American trypanosome, Trypanosoma cruzi, have the capacity to synthesize vitamin C and show that this reaction occurs in a unique single-membrane organelle, the glycosome.

RNA interference identifies two hydroperoxide metabolizing enzymes that are essential to the bloodstream form of the african trypanosome.

Detoxification of hydroperoxides in trypanosomes is mediated by a series of linked redox pathways that are dependent on the parasite-specific thiol trypanothione for reducing equivalents. These pathways are characterized by differences in subcellular location, electron transport molecules, and substrate specificity. To determine the functional significance of the enzymes involved, we have used a tetracycline-inducible RNA interference system to down-regulate expression of each of the corresponding transcripts in bloodstream form Trypanosoma brucei.

Proteolytic inhibition of Salmonella enterica serovar typhimurium-induced activation of the mitogen-activated protein kinases ERK and JNK in cultured human intestinal cells.

Bromelain, a mixture of cysteine proteases from pineapple stems, blocks signaling by the mitogen-activated protein (MAP) kinases extracellular regulated kinase 1 (ERK-1) and ERK-2, inhibits inflammation, and protects against enterotoxigenic Escherichia coli infection. In this study, we examined the effect of bromelain on Salmonella enterica serovar Typhimurium infection, since an important feature of its pathogenesis is its ability to induce activation of ERK-1 and ERK-2, which leads to internalization of bacteria and induction of inflammatory responses. Our results show that bromelain dose dependently blocks serovar Typhimurium-induced ERK-1, ERK-2, and c-Jun NH(2)-terminal kinase (JNK) activation in Caco-2 cells.