Publications by authors named "F Brad Johnson"

2,026 Publications

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Novel Chemically Modified Curcumin (CMC) Derivatives Inhibit Tyrosinase Activity and Melanin Synthesis in B16F10 Mouse Melanoma Cells.

Biomolecules 2021 Apr 30;11(5). Epub 2021 Apr 30.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, USA.

Skin hyperpigmentation disorders arise due to excessive production of the macromolecular pigment melanin catalyzed by the enzyme tyrosinase. Recently, the therapeutic use of curcumin for inhibiting tyrosinase activity and production of melanin have been recognized, but poor stability and solubility have limited its use, which has inspired synthesis of curcumin analogs. Here, we investigated four novel chemically modified curcumin (CMC) derivatives (CMC2.14, CMC2.5, CMC2.23 and CMC2.24) and compared them to the parent compound curcumin (PC) for inhibition of in vitro tyrosinase activity using two substrates for monophenolase and diphenolase activities of the enzyme and for diminution of cellular melanogenesis. Enzyme kinetics were analyzed using Lineweaver-Burk and Dixon plots and nonlinear curve-fitting to determine the mechanism for tyrosinase inhibition. Copper chelating activity, using pyrocatechol violet dye indicator assay, and antioxidant activity, using a DPPH radical scavenging assay, were also conducted. Next, the capacity of these derivatives to inhibit tyrosinase-catalyzed melanogenesis was studied in B16F10 mouse melanoma cells and the mechanisms of inhibition were elucidated. Inhibition mechanisms were studied by measuring intracellular tyrosinase activity, cell-free and intracellular α-glucosidase enzyme activity, and effects on MITF protein level and cAMP maturation factor. Our results showed that CMC2.24 showed the greatest efficacy as a tyrosinase inhibitor of all the CMCs and was better than PC as well as a popular tyrosinase inhibitor-kojic acid. Both CMC2.24 and CMC2.23 inhibited tyrosinase enzyme activity by a mixed mode of inhibition with a predominant competitive mode. In addition, CMC2.24 as well as CMC2.23 showed a comparable robust efficacy in inhibiting melanogenesis in cultured melanocytes. Furthermore, after removal of CMC2.24 or CMC2.23 from the medium, we could demonstrate a partial recovery of the suppressed intracellular tyrosinase activity in the melanocytes. Our results provide a proof-of-principle for the novel use of the CMCs that shows them to be far superior to the parent compound, curcumin, for skin depigmentation.
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http://dx.doi.org/10.3390/biom11050674DOI Listing
April 2021

Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice.

Clin Pharmacol Drug Dev 2021 Apr 19. Epub 2021 Apr 19.

Amicus Therapeutics, Inc., Cranbury, New Jersey, USA.

Approved therapies for Fabry disease (FD) include migalastat, an oral pharmacological chaperone, and agalsidase beta and agalsidase alfa, 2 forms of enzyme replacement therapy. Broad tissue distribution may be beneficial for clinical efficacy in FD, which has severe manifestations in multiple organs. Here, migalastat and agalsidase beta biodistribution were assessed in mice and modeled using physiologically based pharmacokinetic (PBPK) analysis, and migalastat biodistribution was subsequently extrapolated to humans. In mice, migalastat concentration was highest in kidneys and the small intestine, 2 FD-relevant organs. Agalsidase beta was predominantly sequestered in the liver and spleen (organs unaffected in FD). PBPK modeling predicted that migalastat 123 mg every other day resulted in concentrations exceeding the in vitro half-maximal effective concentration in kidneys, small intestine, skin, heart, and liver in human subjects. However, extrapolation of mouse agalsidase beta concentrations to humans was unsuccessful. In conclusion, migalastat may distribute to tissues that are inaccessible to intravenous agalsidase beta in mice, and extrapolation of mouse migalastat concentrations to humans showed adequate tissue penetration, particularly in FD-relevant organs.
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http://dx.doi.org/10.1002/cpdd.941DOI Listing
April 2021

Outcomes of patients with oropharyngeal squamous cell carcinoma treated with induction chemotherapy followed by concurrent chemoradiation compared with those treated with concurrent chemoradiation.

Cancer 2021 Apr 19. Epub 2021 Apr 19.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Induction chemotherapy (IC) has been associated with a decreased risk of distant metastasis in locally advanced head and neck squamous cell carcinoma. However, its role in the treatment of oropharyngeal squamous cell carcinoma (OPSCC) is not well established.

Methods: The outcomes of patients with OPSCC treated with IC followed by concurrent chemoradiation (CRT) were compared with the outcomes of those treated with CRT alone. The primary outcome was overall survival (OS), and the secondary end points were the times to locoregional and distant recurrence.

Results: In an existing database, 585 patients met the inclusion criteria: 137 received IC plus CRT, and 448 received CRT. Most patients were positive for human papillomavirus (HPV; 90.9%). Patients receiving IC were more likely to present with a higher T stage, a higher N stage, and low neck disease. The 3-year OS rate was significantly lower in patients receiving IC (75.7%) versus CRT alone (92.9%). In a multicovariate analysis, receipt of IC (adjusted hazard ratio [aHR], 3.4; P < .001), HPV tumor status (aHR, 0.36; P = .002), and receipt of concurrent cetuximab (aHR, 2.7; P = .002) were independently associated with OS. The risk of distant metastasis was also significantly higher in IC patients (aHR, 2.8; P = .001), whereas an HPV-positive tumor status (aHR, 0.44; P = .032) and completion of therapy (aHR, 0.51; P = .034) were associated with a lower risk of distant metastasis. In HPV-positive patients, IC remained associated with distant metastatic progression (aHR, 2.6; P = .004) but not OS.

Conclusions: In contrast to prior studies, IC was independently associated with worse OS and a higher risk of distant metastasis in patients with OPSCC. Future studies are needed to validate these findings.
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http://dx.doi.org/10.1002/cncr.33491DOI Listing
April 2021

An Attack on Zawadzki's Quantum Authentication Scheme.

Entropy (Basel) 2021 Mar 25;23(4). Epub 2021 Mar 25.

MACIMTE, Universidad Rey Juan Carlos, 28933 Madrid, Spain.

Identification schemes are interactive cryptographic protocols typically involving two parties, a prover, who wants to provide evidence of their identity and a verifier, who checks the provided evidence and decides whether or not it comes from the intended prover. Given the growing interest in quantum computation, it is indeed desirable to have explicit designs for achieving user identification through quantum resources. In this paper, we comment on a recent proposal for quantum identity authentication from Zawadzki. We discuss the applicability of the theoretical impossibility results from Lo, Colbeck and Buhrman et al. and formally prove that the protocol must necessarily be insecure. Moreover, to better illustrate our insecurity claim, we present an attack on Zawadzki's protocol and show that by using a simple strategy an adversary may indeed obtain relevant information on the shared identification secret. Specifically, through the use of the principal of conclusive exclusion on quantum measurements, our attack geometrically reduces the key space resulting in the claimed logarithmic security being reduced effectively by a factor of two after only three verification attempts.
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http://dx.doi.org/10.3390/e23040389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064377PMC
March 2021