المؤلفون: Sullivan, Francis X.

المصدر: America Magazine: The Jesuit Review of Faith & Culture; Nov2020, Vol. 223 Issue 6, p50-53, 4p, 1 Black and White Photograph

مستخلص: The author reflects on sexual abuse of minors by Catholic priests. Topics discussed list of Jesuits credibly accused of the sexual abuse of minors issued by the U.S. Central and Southern Province in 2018 including Thomas J. Hidding and Vincent Malatesta, names of notorious abusers included in the list issued by the Diocese of Dallas, and lawsuit filed by his classmate Mike against the Dallas Jesuit.

المؤلفون: Guarnieri, Anna, Chicarelli, Mark, Cable, Louann, Bouhana, Karyn, Sullivan, Francis, Ball, Howard, Sachs, Jessica, Winski, Shannon, Robinson, John

المصدر: Blood; November 2021, Vol. 138 Issue: 1, Number 1 Supplement 1 p4595-4595, 1p

مستخلص: The molecular pathogenesis of Systemic Mastocytosis (SM) is driven by mutations in the KIT gene, with 95% of patients having a mutation in exon 17, D816V, leading to constant proliferation of mast cells (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Targeted therapeutics have revealed clinical activity in these patients, but toxicities such as cognitive effects, intracranial hemorrhage, hypertension, and edema may limit dosing and availability of these therapies. While the exact cause of these effects is difficult to determine, numerous closely related kinases, such as wild type PDGFRα, PDGFRβ, KIT, VEGFR2 (KDR), and CSF1R (FMS), are considered to be anti-targets, with previous evidence of their inhibition linked to observed clinical toxicities (Liu & Kurzrock, 2015; Giles et al., 2009; Jayson et al., 2005). Bezuclastinib (CGT9486) was designed to selectively inhibit KIT D816V versus these other closely related kinase anti-targets. Additionally, we demonstrate that bezuclastinib has minimal brain penetration, together with no observed CNS-related toxicities in nonclinical studies. Herein, we present results from cell-based kinase profiling assays, which demonstrate that bezuclastinib has a significant and unique selectivity to KIT D816V relative to the aforementioned kinases when tested head-to-head against other clinically relevant compounds in SM. Additionally, a similar selectivity profile was observed for a broader panel of kinases, ion channels, transporters, and enzymes, which will be presented here, including drug concentrations and target engagement achieved with recent in vivo studies. Importantly, we also show that bezuclastinib has minimal brain penetration, a preferred feature of an anti-Kit molecule due to CNS-related adverse events observed in these indications. In a tissue distribution study performed in rats, bezuclastinib shows a brain:plasma ratio <0.1 following 3 day administration at 25 mg/kg, a dose that closely correlates with clinical plasma exposure. This was supported functionally by assessing neurobehavioral effects of bezuclastinib at dose levels up to 100 mg/kg in rats which showed no CNS related effects. This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors (Trent et al, 2020), supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM with additional clinical studies planned in non-advanced SM and imatinib-resistant GIST.

المؤلفون: Guarnieri, Anna, Chicarelli, Mark, Cable, Louann, Bouhana, Karyn, Sullivan, Francis, Ball, Howard, Sachs, Jessica, Winski, Shannon, Robinson, John

المصدر: Blood; November 2021, Vol. 138 Issue: Supplement 1 p4595-4595, 1p

مستخلص: Guarnieri: Cogent Biosciences: Current Employment. Cable: Cogent Biosciences: Current Employment. Bouhana: Cogent Biosciences: Current Employment. Sullivan: Cogent Biosciences: Current Employment. Ball: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. Winski: Cogent Biosciences: Current Employment. Robinson: Cogent Biosciences: Current Employment.

المؤلفون: Davies, Kurtis D., Cable, P. LouAnn, Garrus, Jennifer E., Sullivan, Francis X., von Carlowitz, Ira, Huerou, Yvan Le, Wallace, Eli, Woessner, Richard D., Gross, Stefan

المصدر: Cancer Biology and Therapy; November 2011, Vol. 12 Issue: 9 p788-796, 9p

مستخلص: Inhibition of the checkpoint kinase Chk1, both as a monotherapy and in combination with DNA damaging cytotoxics, is a promising therapeutic approach for the treatment of a wide array of human cancers. However, much remains to be elucidated in regard to the patient populations that will respond best to a Chk1 inhibitor and the optimal therapeutics to combine with a Chk1 inhibitor. In an effort to discover sensitizing mutations and novel combination strategies for Chk1 inhibition, an siRNA screen was performed in combination with the selective Chk1 inhibitor AR458323. This screen employed a custom made library of siRNAs targeting 195 genes, most of which are involved in cell-cycle control or DNA damage repair. One of the most prominent and consistent hits across runs of the screen performed in three different cancer cell lines was Wee1 kinase. MK-1775 is a small molecule inhibitor of Wee1 that is currently in early stage clinical trials. In confirmation of the results obtained from the siRNA screen, AR458323 and MK-1775 synergistically inhibited proliferation in multiple cancer cell types. This antiproliferative effect correlated with a synergistic induction of apoptosis. In cellular mechanistic studies, the combination of the two molecules resulted in dramatic decreases in inhibitory phosphorylation of cyclin-dependent kinases, an increase in DNA damage, alterations in cell-cycle profile, and collapse of DNA synthesis. In conclusion, the clinical combination of a Chk1 inhibitor and a Wee1 inhibitor holds promise as an effective treatment strategy for cancer.

المؤلفون: Olland, Andrea M., Underwood, Kathryn W., Czerwinski, Robert M., Lo, Mei-Chu, Aulabaugh, Ann, Bard, Joel, Stahl, Mark L., Somers, William S., Sullivan, Francis X., Chopra, Rajiv

المصدر: Journal of Biological Chemistry; February 2002, Vol. 277 Issue: 5 p3698-3707, 10p

مستخلص: The nadDgene, encoding the enzyme nicotinic acid mononucleotide (NaMN) adenylyltransferase (AT), is essential for the synthesis of NAD and subsequent viability of the cell. The nadDgene in Bacillus subtilis(yqeJ) was identified by sequence homology with other bacterial nadDgenes and by biochemical characterization of the gene product. NaMN AT catalyzes the reversible adenylation of both NaMN and the nicotinamide mononucleotide (NMN) but shows specificity for the nicotinate. In contrast to other known NMN ATs, biophysical characterizations reveal it to be a dimer. The NaMN AT crystal structure was determined for both the apo enzyme and product-bound form, to 2.1 and 3.2 Å, respectively. The structures reveal a “functional” dimer conserved in both crystal forms and a monomer fold common to members of the nucleotidyl-transferase α/β phosphodiesterase superfamily. A structural comparison with family members suggests a new conserved motif (SXXXX(R/K)) at the N terminus of an α-helix, which is not part of the shared fold. Interactions of the nicotinic acid with backbone atoms indicate the structural basis for specificity.

المؤلفون: Menon, Saurabh, Stahl, Mark, Kumar, Ravindra, Xu, Guang-Yi, Sullivan, Francis

المصدر: Journal of Biological Chemistry; September 1999, Vol. 274 Issue: 38 p26743-26750, 8p

مستخلص: Recently the genes encoding the human and Escherichia coliGDP-mannose dehydratase and GDP-fucose synthetase (GFS) protein have been cloned and it has been shown that these two proteins alone are sufficient to convert GDP mannose to GDP fucose in vitro. GDP-fucose synthetase from E. coliis a novel dual function enzyme in that it catalyzes epimerizations and a reduction reaction at the same active site. This aspect separates fucose biosynthesis from that of other deoxy and dideoxy sugars in which the epimerase and reductase activities are present on separate enzymes encoded by separate genes. By NMR spectroscopy we have shown that GFS catalyzes the stereospecific hydride transfer of the ProS hydrogen from NADPH to carbon 4 of the mannose sugar. This is consistent with the stereospecificity observed for other members of the short chain dehydrogenase reductase family of enzymes of which GFS is a member. Additionally the enzyme is able to catalyze the epimerization reaction in the absence of NADP or NADPH. The kinetic mechanism of GFS as determined by product inhibition and fluorescence binding studies is consistent with a random mechanism. The dissociation constants determined from fluorescence studies indicate that the enzyme displays a 40-fold stronger affinity for the substrate NADPH as compared with the product NADP and utilizes NADPH preferentially as compared with NADH. This study on GFS, a unique member of the short chain dehydrogenase reductase family, coupled with that of its recently published crystal structure should aid in the development of antimicrobial or anti-inflammatory compounds that act by blocking selectin-mediated cell adhesion.

المؤلفون: Hagler, James, Sullivan, Francis

المصدر: Proceedings of the American Mathematical Society; 1980, Vol. 78 Issue: 4 p497-503, 7p

مستخلص: If a Banach space E has an equivalent smooth norm, then every bounded sequence in $ {E^\ast}$ converging subsequence. Generalizations of this result are obtained.

المؤلفون: Kumar, Ravindra, Camphausen, Raymond T., Sullivan, Francis X., Cumming, Dale A.

المصدر: Blood; November 1996, Vol. 88 Issue: 10 p3872-3879, 8p

مستخلص: P-selectin glycoprotein ligand-1 (PSGL-1) is a high-affinity counterreceptor for P-selectin on myeloid cells and activated T-cells. In addition, PSGL-1 can serve, both in vitro and in vivo, as an E-selectin ligand. Appropriate glycosylation of PSGL-1 is crucial for binding to P-selectin. Functional PSGL-1 is known to bear sialyl lewis X (SLex) or a closely related oligosaccharide. In this study, we show that Chinese hamster ovary (CHO) cells expressing PSGL-1 and fucosyltrans-ferase show a dramatic increase in binding to P-selectin when transfected with “core2” transferase, the enzyme that initiates branching of O-linked glycans. Moreover, only PSGL-1 from core2 transfectant CHO cells can be affinity-captured with P-selectin, suggesting that branched O-linked glycans are required for high-affinity binding to P-selectin. Analysis of PSGL-1 -derived O-linked oligosaccharides produced in core2 transfected cells shows the presence of more elaborated glycans. Interestingly, transfection of core2 in these cells does not alter binding to E-selectin.

المؤلفون: Bernal, Javier, Sullivan, Francis

المصدر: Proceedings of the American Mathematical Society; 1984, Vol. 90 Issue: 4 p550-554, 5p

مستخلص: We prove that given a Hilbert space $ \left( {E,\vert\vert \cdot \vert\vert} \right)$ a norm on $ E$, $ 1/\beta \left\vert x \right\vert \leqslant \left\Vert x \right\Vert \leqslant \left\vert x \right\vert$, if $ 1 \leqslant \beta < \sqrt 2 $ satisfies a convexity property from which normal structure follows.

المؤلفون: Epstein, John H, Sullivan, Francis J, Epstein, William L

المصدر: Journal of Investigative Dermatology; February 1961, Vol. 36 Issue: 2 p73-77, 5p