The electronic properties of small molecules can be calculated quickly and with a reasonable degree of accuracy using semiempirical QM methods. In this study a set of QM properties derived from frontier electron theory have been used to produce a predictive model of the dissociation constants of phenols, benzoic acids and aliphatic carboxylic acids. The pK a values and structures of nearly 500 compounds were extracted from the Physprop database for this purpose. Multiple linear regression was used to search for relationships between pK a and the calculated QM properties. In most cases only a single independent variable, electrophilic superdelocalisability, was needed to produce a good model of pK a . The advantages of our approach are in the speed of calculation and the simplicity of the resultant models. The merits of using semiempirical methods to predict pK a are discussed in relation to previous studies.
During haematopoiesis, haematopoietic stem cells differentiate into restricted potential progenitors before maturing into the many lineages required for oxygen transport, wound healing and immune response. We have updated Haemopedia, a database of gene-expression profiles from a broad spectrum of haematopoietic cells, to include RNA-seq gene-expression data from both mice and humans. The Haemopedia RNA-seq data set covers a wide range of lineages and progenitors, with 57 mouse blood cell types (flow sorted populations from healthy mice) and 12 human blood cell types. This data set has been made accessible for exploration and analysis, to researchers and clinicians with limited bioinformatics experience, on our online portal Haemosphere: https://www.haemosphere.org. Haemosphere also includes nine other publicly available high-quality data sets relevant to haematopoiesis. We have added the ability to compare gene expression across data sets and species by curating data sets with shared lineage designations or to view expression gene vs gene, with all plots available for download by the user.
Acute myeloid leukemia (AML) is a biologically heterogeneous group of related diseases in urgent need of better therapeutic options. Despite this heterogeneity, overexpression of the interleukin (IL)-3 receptor α-chain (IL-3 Rα/CD123) on both the blast and leukemic stem cell (LSC) populations is a common occurrence, a finding that has generated wide interest in devising new therapeutic approaches that target CD123 in AML patients. We report here the development of CSL362, a monoclonal antibody to CD123 that has been humanized, affinity-matured and Fc-engineered for increased affinity for human CD16 (FcγRIIIa). In vitro studies demonstrated that CSL362 potently induces antibody-dependent cell-mediated cytotoxicity of both AML blasts and CD34(+)CD38(-)CD123(+) LSC by NK cells. Importantly, CSL362 was highly effective in vivo reducing leukemic cell growth in AML xenograft mouse models and potently depleting plasmacytoid dendritic cells and basophils in cynomolgus monkeys. Significantly, we demonstrated CSL362-dependent autologous depletion of AML blasts ex vivo, indicating that CSL362 enables the efficient killing of AML cells by the patient's own NK cells. These studies offer a new therapeutic option for AML patients with adequate NK-cell function and warrant the clinical development of CSL362 for the treatment of AML.
The pK a of a compound directly influences its biopharmaceutical profile. This article describes the development of a method for estimating pK a values for a number of nitrogen containing chemical structures using semiempirical QM properties derived from frontier electron theory. Typically, the property giving the best correlation with pK a was the electrophilic superdelocalisability of the nitrogen atom resulting in regression equations with r 2 values up to 0.94. The advantages of this technique are in the simplicity of the models and the speed of calculation, suggesting that this method could be widely applied to the estimation of pK a values. The success of this approach is discussed in relation to other methods.
The Glutathione S-transferases (GSTs) form a group of multi-gene isoenzymes involved in the cellular detoxification of both xenobiotic and endobiotic compounds. GSTs have been divided into a number of subclasses, alpha (α), mu {μ), pi (π), and theta (θ). The classification was made on the basis of sequence similarity and immunological cross-reactivity. GSTs show a high level of specificity toward GSH but the electrophilic second substrate can vary significantly both between and within the classes in spite of their sequence similarity. X-ray crystallography and site-directed mutagenesis studies have together elucidated the structure and mechanism of GSTs. Catalysis occurs by conjugation with glutathione (GSH) and the less toxic and more hydrophilic products can then be partially metabolised and excreted. This invaluable service is however disadvantageous during chemotherapy where GSTs have been associated with multi-drug resistance of tumour cells. Levels of expression of different isoforms of GSTs are tissue specific. The variations in expression between normal and tumour cells are of interest and in most cases the levels of GSTs are increased, especially n-GST. Understanding the complex role that GSTs play in drug resistance begins with determining the pattern of isoform expression and the substrate specificities of each isoform. The use of isozyme-specific, GSH analogues as inhibitors to modulate GST activity during chemotherapy is a promising strategy in the battle against cancer. This review attempts to provide a detailed overview of the literature concerning the different classes of GSTs, their function and mechanism and the use of GSTs as therapeutic targets for disease as current at the time of submission.
Homophilic engagement of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) induces 'outside-in' signal transduction that results in phosphorylation events and recruitment and activation of signalling molecules. The formation of signalling scaffolds with PECAM-1 are important signalling events that modulate platelet secretion, aggregation and platelet thrombus formation. In this study, we describe a novel interaction between PECAM-1 and cytosolic calmodulin (CaM) in platelets. Reciprocal co-immunoprecipitation studies revealed that cytosolic CaM is constitutively associated with PECAM-1 in resting, thrombin activated and aggregated human platelets. Our studies demonstrate that CaM directly interacts with a PECAM-1 peptide (594-604) C595A containing the sequences 594 KAFYLRKAKAK 604 . This CaM:PECAM-1 interaction has a threefold higher affinity than CaM:GPVI interaction. It is potentiated by the addition of calcium ions, and dissociated by the CaM inhibitor, trifluoperazine. Treatment of platelets with CaM inhibitors triggers cleavage of PECAM-1 in a time-and dose-dependent manner. Furthermore, this membrane proximal portion of PECAM-1 is conserved across mammalian species and the helical representation of basic/ hydrophobic residues reveals a charge distribution analogous to other CaM-binding motifs in other proteins. Taken together, these results suggest that this highly charged cluster of amino acids in the PECAM-1 cytoplasmic domain directly interacts with CaM and this novel interaction appears to regulate cleavage of PECAM-1.
SummaryMDX-1097 is an antibody specific for a unique B cell antigen called kappa myeloma antigen (KMA) that consists of cell membrane-associated free kappa light chain (jFLC). KMA was detected on kappa human multiple myeloma cell lines (jHMCLs), on plasma cells (PCs) from kappa multiple myeloma (jMM) patients and on jPC dyscrasia tissue cryosections. In primary jMM samples, KMA was present on CD38+ cells that were CD138 and CD45 positive and/or negative. MDX-1097 exhibited a higher affinity for KMA compared to jFLC and the latter did not abrogate binding to KMA. MDX-1097-mediated antibody-dependent cellular cytotoxicity (ADCC) and in vitro exposure of target cells to the immunomodulatory drug lenalidomide resulted in increased KMA expression and ADCC. Also, in vitro exposure of peripheral blood mononuclear cells (PBMCs) to lenalidomide enhanced MDX-1097-mediated ADCC. PBMCs obtained from myeloma patients after lenalidomide therapy elicited significantly higher levels of MDX-1097-mediated ADCC than cells obtained prior to lenalidomide treatment. These data establish KMA as a relevant cell surface antigen on MM cells that can be targeted by MDX-1097. The ADCC-inducing capacity of MDX-1097 and its potentiation by lenalidomide provide a powerful rationale for clinical evaluation of MDX-1097 alone and in combination with lenalidomide.
The variable-temperature 90.1 -MHz 13C-{lH} and/or 145.87-MHz 31P-{1H} n.m.r. spectra of dicarbonyl ( qs-hexaet hyl benzene) (t hiocarbony1)chromium (o), (4), dicarbonyl(qs-hexaethyl benzene) -(trimethy1phosphine)c hromium (o), (5), dicarbonyl ( qs-hexaethylbenzene) (triet hyl phosphine)chromium (0) , (6), dicarbonyl (qs-hexaet hyl benzene) (triet hyl phosphine) molybdenum (o), ( 7 ) , dicarbonyl( qs-hexaethyl benzene) (triphenyl phosphite)chromium (o), (S), dicarbonyl (qs-hexaethylbenzene) (q2-maleic anhydride)chromium(o), (1 0), dicarbonyl(q"-hexaethylbenzene) ( q2-maleic anhydride) molybdenum(o), (1 1 ), and (qs-cyclopentadienyl) (qs-hexaethylbenzene) iron (11) hexafluorophosphate, (1 2), have been observed and subjected to lineshape analysis. In a number of cases, multiple heb stereoisomers are found to coexist in equilibrium in solution at low temperatures. For all the hexaethylbenzene (heb) complexes examined, the n.m.r. spectra can be satisfactorily analysed without the need t o invoke hindered rotation about the metal-arene bond and coalescence phenomena observed in the spectra are attributed to the onset of rapid rotation of the ethyl groups about the benzene ring and heb stereoisomerisation. Barriers to site exchange
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.