ORCID Profile
0000-0002-9162-477X
Current Organisations
Macquarie University
,
Yale University
,
Harvard Medical School
,
Northwell Health
,
Columbia University
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Publisher: CSIRO Publishing
Date: 2018
DOI: 10.1071/CH18416
Abstract: Sir Derek Barton’s seminal work on steroid conformational analysis opened up a new era of enquiry into how the preferred conformation of any molecule could have profound effects on its physical–chemical properties and activities. Conformation-based effects on molecular activity and reactivity continue to manifest, with one key area of investigation currently focussed on conformational entropy in driving protein–ligand interactions. Carrying on from Barton’s initial insight on natural product conformational properties, new questions now address how conformational flexibility within a bioactive natural product structural framework (reasonable chaos), can be directed to confer dynamically new protein–ligand interactions beyond the basic lock–key model (imaginative order). Here we summarise our work on exploring conformational ersity from fluorinated natural product fragments, and how this approach of conformation-coupled ersity-oriented synthesis can be used to iteratively derive ligands with enhanced specificity against highly homologous protein domains. Our results demonstrate that the conformation entropic states of highly conserved protein domains differ significantly, and this conformational ersity, beyond primary sequence analysis, can be duly captured and exploited by natural-product derived ligands with complementary conformational dynamics for enhancing recognition specificity in drug lead discovery.
Publisher: Oxford University Press (OUP)
Date: 22-11-2018
Publisher: Elsevier BV
Date: 03-2011
Publisher: Massachusetts Medical Society
Date: 04-10-2012
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1OB90070F
Publisher: Oxford University Press (OUP)
Date: 04-06-2013
DOI: 10.1093/HMG/DDT177
Publisher: MDPI AG
Date: 03-2013
Publisher: Oxford University Press (OUP)
Date: 13-06-2021
DOI: 10.1093/EURHEARTJ/EHAB309
Abstract: The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in in iduals without previous CVD or diabetes aged 40–69 years in Europe. We derived risk prediction models using in idual-participant data from 45 cohorts in 13 countries (677 684 in iduals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 in iduals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 in iduals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65–0.68) to 0.81 (0.76–0.86). Predicted CVD risk varied several-fold across European regions. For ex le, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low-risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries. SCORE2—a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations—enhances the identification of in iduals at higher risk of developing CVD across Europe.
Publisher: MDPI AG
Date: 30-01-2023
Abstract: Breakthrough research in the field of immune checkpoint inhibitors and the development of a human papilloma virus vaccine triggered a plethora of research in the field of cancer immunotherapy. Both had significant effects on the treatment of head and neck squamous cell carcinoma. The advent of preclinical models and multidisciplinary approaches including bioinformatics, genetic engineering, clinical oncology, and immunology helped in the development of tumour-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy. Here, we discuss different immunotherapies such as adoptive T-cell transfer, immune checkpoint inhibitors, interleukins, and cancer vaccines for the treatment of head and neck cancer. This review showcases the intrinsic relation between the understanding and implementation of basic biology and clinical practice. We also address potential limitations of each immunotherapy approach and the advantages of personalized immunotherapy. Overall, the aim of this review is to encourage further research in the field of immunotherapy for head and neck cancer.
Publisher: Elsevier BV
Date: 2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2022
DOI: 10.1161/CIRCULATIONAHA.122.060700
Abstract: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Observational analyses were conducted using in idual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values or mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR mL·min –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
Publisher: MDPI AG
Date: 31-10-2017
Publisher: Elsevier BV
Date: 10-2019
Publisher: American Chemical Society (ACS)
Date: 12-01-2016
Publisher: Oxford University Press (OUP)
Date: 23-07-2012
DOI: 10.1093/IJE/DYS086
Publisher: Elsevier BV
Date: 11-2012
Publisher: Springer Science and Business Media LLC
Date: 06-02-2020
Publisher: Elsevier BV
Date: 03-2014
Publisher: Elsevier BV
Date: 12-2022
Publisher: American Medical Association (AMA)
Date: 07-07-2015
Publisher: Wiley
Date: 20-12-2014
Publisher: American Chemical Society (ACS)
Date: 06-03-2019
DOI: 10.1021/ACSCHEMBIO.8B01004
Abstract: Artemisinins are the most potent and safe antimalarials available. Despite their clinical potential, no human target for the artemisinins is known. The unbiased interrogation of several human cDNA libraries, displayed on bacteriophage T7, revealed a single human target of artesunate the intrinsically disordered Bcl-2 antagonist of cell death promoter (BAD). We show that artesunate inhibits the phosphorylation of BAD, thereby promoting the formation of the proapoptotic BAD/Bcl-xL complex and the subsequent intrinsic apoptotic cascade involving cytochrome c release, PARP cleavage, caspase activation, and ultimately cell death. This unanticipated role of BAD as a possible drug target of artesunate points to direct clinical exploitation of artemisinins in the Bcl-xL life/death switch and that artesunate's anticancer activity is, at least in part, independent of reactive oxygen species.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9MD00128J
Abstract: One of chemistry's grand challenges is to find a function for every known metabolite. We explore the opportunity for artificial intelligence to provide rationale interrogation of metabolites to predict their function.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB00129K
Abstract: Enhanced selectivity for homologous ATP sites by composite chemical and conformational perturbation by stereospecific fluorination.
Publisher: Elsevier BV
Date: 06-2010
Publisher: American Chemical Society (ACS)
Date: 27-01-2018
Abstract: (-)-Balanol is an adenosine triphosphate mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with limited selectivity. While PKA is known as a tumor promoter, PKC isozymes can be tumor promoters or suppressors. In particular, PKCε is frequently involved in tumorigenesis and a potential target for anticancer drugs. We recently reported that stereospecific fluorination of balanol yielded a balanoid with enhanced selectivity for PKCε over other PKC isozymes and PKA, although the global fluorine effect behind the selectivity enhancement is not fully understood. Interestingly, in contrast to PKA, PKCε is more sensitive to this fluorine effect. Here we investigate the global fluorine effect on the different binding responses of PKCε and PKA to balanoids using molecular dynamics (MD) simulations. For the first time to the best of our knowledge, we found that a structurally equivalent residue in each kinase, Thr184 in PKA and Ala549 in PKCε, is essential for the different binding responses. Furthermore, the study revealed that the invariant Lys, Lys73 in PKA and Lys437 in PKCε, already known to have a crucial role in the catalytic activity of kinases, serves as the main anchor for balanol binding. Overall, while Thr184 in PKA attenuates the effect of fluorination, Ala549 permits remote response of PKCε to fluorine substitution, with implications for rational design of future balanol-based PKCε inhibitors.
Publisher: American Chemical Society (ACS)
Date: 19-04-2012
DOI: 10.1021/ED200533U
Publisher: Public Library of Science (PLoS)
Date: 30-07-2013
Publisher: MDPI AG
Date: 26-12-2021
DOI: 10.3390/IJMS22010160
Abstract: The differentiation of human adipose derived stem cells toward a neural phenotype by small molecules has been a vogue topic in the last decade. The characterization of the produced cells has been explored on a broad scale, examining morphological and specific surface protein markers however, the lack of insight into the expression of functional proteins and their interactive partners is required to further understand the extent of the process. The phenotypic characterization by proteomic profiling allows for a substantial in-depth analysis of the molecular machinery induced and directing the cellular changes through the process. Herein we describe the temporal analysis and quantitative profiling of neural differentiating human adipose-derived stem cells after sub-proteome enrichment using a bisindolylmaleimide chemical probe. The results show that proteins enriched by the Bis-probe were identified reproducibly with 133, 118, 126 and 89 proteins identified at timepoints 0, 1, 6 and 12, respectively. Each temporal timepoint presented several shared and unique proteins relative to neural differentiation and their interactivity. The major protein classes enriched and quantified were enzymes, structural and ribosomal proteins that are integral to differentiation pathways. There were 42 uniquely identified enzymes identified in the cells, many acting as hubs in the networks with several interactions across the network modulating key biological pathways. From the cohort, it was found by gene ontology analysis that 18 enzymes had direct involvement with neurogenic differentiation.
Publisher: Mary Ann Liebert Inc
Date: 02-2014
Publisher: Springer Science and Business Media LLC
Date: 02-2019
Publisher: Elsevier BV
Date: 04-2018
Location: United States of America
No related grants have been discovered for Karina Davidson.