Correlation between daily life aluminium exposure and breast cancer risk: A systematic review.

BACKGROUND: Epidemiological data indicate that the role of environmental factors on breast cancer (BC) incidence remains undetermined. Our daily life exposure to aluminium (Al) is suspected to influence BC development. This review proposes a state of the art on the association between Al and BC risk combined with a critical point of view on the subject. METHODS: We searched the PubMed database using terms related to Al and BC up to November 18, 2022. Reports were eligible if they were cohort or case-control studies or meta-analyses. FINDINGS: Six studies focused on the relationship between deodorant and antiperspirant use and BC incidence and didn't produce consistent results. Among 13 studies relating Al content in mammary tissues and BC risk, results are not unanimous to validate higher Al content in tumor tissues compared to healthy ones. We detail parameters that could explain this conclusion: the absence of statistical adjustments on BC risk factors in studies, the confusion between deodorant and antiperspirant terms, the non-assessment of global Al exposure, and the focus on Al in mammary tissues whereas a profile of several metals seems more appropriate. The clinical studies are retrospective. They were carried out on small cohorts and without a long follow-up. On the other hand, studies on cell lines have shown the carcinogenic potential of aluminum. Moreover, studies considered BC as a unique group whereas BC is a heterogeneous disease with multiple tumor subtypes determining the tumor aggressiveness. CONCLUSION: In light of the precautionary principle and based on the data obtained, it is better to avoid antiperspirants that contain Al. Deodorants without aluminum are not implicated in breast cancer, either clinically or fundamentally.

The ADHD rating scale-IV preschool version: Factor structure, reliability, validity, and standardisation in a Danish community sample.

BACKGROUND: ADHD is a debilitating disorder with symptoms often appearing in early childhood. To facilitate early identification, developmentally appropriate and validated assessment tools for the preschool-age are needed. AIMS: The current study aims to examine the psychometric properties of the ADHD Rating Scale (RS)-IV Preschool Version (-P) in a Danish community sample and provide national standardisation data. METHODS AND PROCEDURES: Parents (n = 916) and kindergarten teachers (n = 275) of preschool children, aged 3-5 years, completed the ADHD RS-IV-P. OUTCOMES AND RESULTS: Confirmatory factor analysis indicated that a three-factor model (inattention, hyperactivity, and impulsivity) best fit the data regardless of rater. Scales generally showed acceptable internal consistency, test-retest reliability, inter-rater reliability, and criterion validity. Boys received higher ratings on the ADHD RS-IV-P than girls and younger preschool children were rated as more inattentive than older preschool children. CONCLUSIONS AND IMPLICATIONS: Our findings support the reliability and validity of the ADHD RS-IV-P and a three-factor model of ADHD. However, high factor correlations and similarity in model fit suggest that more research is needed to clarify the organisation of ADHD symptoms in preschool children. Furthermore, the external validity of separate ADHD dimensions at this age should be examined.

New 4-Amino-1,2,3-Triazole Inhibitors of Indoleamine 2,3-Dioxygenase Form a Long-Lived Complex with the Enzyme and Display Exquisite Cellular Potency.

Indoleamine-2,3 dioxygenase 1 (IDO1) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO1 has become an attractive target for cancer treatment. A novel series of highly cell potent IDO1 inhibitors based on a 4-amino-1,2,3-triazole core have been identified. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a noncompetitive kinetic mechanism of action with respect to the tryptophan substrate. In co-complex crystal structures, the compounds bind in the tryptophan pocket and make a direct ligand interaction with the haem iron of the porphyrin cofactor. It is proposed that these data can be rationalised by an ordered-binding mechanism, in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO1-targeted drugs.

5',6'-nucleoside phosphonate analogues architecture: synthesis and comparative evaluation towards metabolic enzymes.

Nucleoside phosphonates have been designed as stable 5'-mononucleotide mimics and are nowadays considered a potent class of antiviral agents. Within cells, they must be metabolised to the corresponding diphosphate to exert their biological activity. In this process, the first phosphorylation step, catalysed by nucleoside monophosphate kinases (NMP kinases), has been proposed as a bottleneck. Herein, we report the synthesis of a series of ribonucleoside phosphonate derivatives isosteric to 5'-mononucleotides, with different degrees of flexibility within the 5',6'-C-C bond, as well as different polarities, through the introduction of hydroxy groups. The influence of these modifications on the capacity of the compounds to act as substrates for appropriate human NMP kinases, involved in nucleic acids metabolism, has been investigated. Low flexibility, as well as an absence of hydroxy groups within the ribose-phosphorus architecture, is critical for efficient phosphotransfer. Among the series of pyrimidine analogues, one derivative was shown to be phosphorylated by human UMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP.

Novel antiviral C5-substituted pyrimidine acyclic nucleoside phosphonates selected as human thymidylate kinase substrates.

Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies. They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases. New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase. Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate-cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovir. Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP. The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC(50) = 3 µM) and against varicella zoster virus in vitro (IC(50) = 0.19 µM), in contrast to the corresponding inactive (Z) derivatives. Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates.

Looking for new pyrimidine acyclic nucleotide analogues designed for phosphorylation by human UMP-CMP kinase.

Human UMP-CMP kinase is involved in the phosphorylation of nucleic acid precursors and also in the activation of antiviral analogues including cidofovir, an acyclic phosphonate compound that mimicks dCMP and shows a broad antiviral spectrum. The binding of ligands to the enzyme was here investigated using a fluorescent probe and a competitive titration assay. At the acceptor site, the enzyme was found to accommodate any base, purine and pyrimidine, including thymidine. A method for screening analogues based on their affinity for the UMP binding site was developed. The affinities of uracil vinylphosphonate derivatives modified in the 5 position were found similar to (d)UMP and (d)CMP and improved when compared to cidofovir.

Enantioselectivity of human AMP, dTMP and UMP-CMP kinases.

L-nucleoside analogues such as lamivudine are active for treating viral infections. Like D-nucleosides, the biological activity of the L-enantiomers requires their stepwise phosphorylation by cellular or viral kinases to give the triphosphate. The enantioselectivity of NMP kinases has not been thoroughly studied, unlike that of deoxyribonucleoside kinases. We have therefore investigated the capacity of L-enantiomers of some natural (d)NMP to act as substrates for the recombinant forms of human uridylate-cytidylate kinase, thymidylate kinase and adenylate kinases 1 and 2. Both cytosolic and mitochondrial adenylate kinases were strictly enantioselective, as they phosphorylated only D-(d)AMP. L-dTMP was a substrate for thymidylate kinase, but with an efficiency 150-fold less than D-dTMP. Both L-dUMP and L-(d)CMP were phosphorylated by UMP-CMP kinase although much less efficiently than their natural counterparts. The stereopreference was conserved with the 2'-azido derivatives of dUMP and dUMP while, unexpectedly, the 2'-azido-D-dCMP was a 4-fold better substrate for UMP-CMP kinase than was CMP. Docking simulations showed that the small differences in the binding of D-(d)NMP to their respective kinases could account for the differences in interactions of the L-isomers with the enzymes. This in vitro information was then used to develop the in vivo activation pathway for L-dT.

Nucleotide binding to human UMP-CMP kinase using fluorescent derivatives -- a screening based on affinity for the UMP-CMP binding site.

Methylanthraniloyl derivatives of ATP and CDP were used in vitro as fluorescent probes for the donor-binding and acceptor-binding sites of human UMP-CMP kinase, a nucleoside salvage pathway kinase. Like all NMP kinases, UMP-CMP kinase binds the phosphodonor, usually ATP, and the NMP at different binding sites. The reaction results from an in-line phosphotransfer from the donor to the acceptor. The probe for the donor site was displaced by the bisubstrate analogs of the Ap5X series (where X = U, dT, A, G), indicating the broad specificity of the acceptor site. Both CMP and dCMP were competitors for the acceptor site probe. To find antimetabolites for antivirus and anticancer therapies, we have developed a method of screening acyclic phosphonate analogs that is based on the affinity of the acceptor-binding site of the human UMP-CMP kinase. Several uracil vinylphosphonate derivatives had affinities for human UMP-CMP kinase similar to those of dUMP and dCMP and better than that of cidofovir, an acyclic nucleoside phosphonate with a broad spectrum of antiviral activities. The uracil derivatives were inhibitors rather than substrates of human UMP-CMP kinase. Also, the 5-halogen-substituted analogs inhibited the human TMP kinase less efficiently. The broad specificity of the enzyme acceptor-binding site is in agreement with a large substrate-binding pocket, as shown by the 2.1 A crystal structure.