Erdafitinib Resensitizes ABCB1-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs.

The development of multidrug resistance (MDR) in cancer patients, which is often associated with the overexpression of ABCB1 (MDR1, P-glycoprotein) in cancer cells, remains a significant problem in cancer chemotherapy. ABCB1 is one of the major adenosine triphosphate (ATP)-binding cassette (ABC) transporters that can actively efflux a range of anticancer drugs out of cancer cells, causing MDR. Given the lack of Food and Drug Administration (FDA)-approved treatment for multidrug-resistant cancers, we explored the prospect of repurposing erdafitinib, the first fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA, to reverse MDR mediated by ABCB1. We discovered that by reducing the function of ABCB1, erdafitinib significantly resensitized ABCB1-overexpressing multidrug-resistant cancer cells to therapeutic drugs at sub-toxic concentrations. Results of erdafitinib-stimulated ABCB1 ATPase activity and in silico docking analysis of erdafitinib binding to the substrate-binding pocket of ABCB1 further support the interaction between erdafitinib and ABCB1. Moreover, our data suggest that ABCB1 is not a major mechanism of resistance to erdafitinib in cancer cells. In conclusion, we revealed an additional action of erdafitinib as a potential treatment option for multidrug-resistant cancers, which should be evaluated in future drug combination trials.

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs.

The development of multidrug resistance (MDR) in cancer patients driven by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells presents one of the most daunting therapeutic complications for clinical scientists to resolve. Despite many novel therapeutic strategies that have been tested over the years, there is still no approved treatment for multidrug-resistant cancers to date. We have recently adopted a drug repurposing approach to identify therapeutic agents that are clinically active and at the same time, capable of reversing multidrug resistance mediated by ABCB1 and ABCG2. In the present study, we investigated the effect of sitravatinib, a novel multitargeted receptor tyrosine kinase inhibitor, on human ABCB1 and ABCG2 in multidrug-resistant cancer cell lines. We discovered that at submicromolar concentrations, sitravatinib re-sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. We found that sitravatinib blocks the drug efflux function of ABCB1 and ABCG2 in a concentration-dependent manner but does not significantly alter the protein expression of ABCB1 or ABCG2 in multidrug-resistant cancer cells. In conclusion, we reveal a potential drug repositioning treatment option for multidrug-resistant cancers by targeting ABCB1 and ABCG2 with sitravatinib and should be further investigated in future clinical trials.

Effects of chitosan oligosaccharides on drug-metabolizing enzymes in rat liver and kidneys.

To investigate the effect of chitosan oligosaccharides (COS) on drug-metabolizing enzymes in rat liver and kidneys, male Spraque-Dawley rats were fed a diet containing 1% or 3% COS for 5 weeks. The activities of cytochrome P450 (CYP) enzymes, UDP-glucurosyltransferase (UGT) and glutathione S-transferase (GST) in the liver and kidneys were determined. Significant decreases in microsomal CYP3A-catalyzed testosterone 6ß-hydroxylation, CYP2C-catalyzed diclofenac 4-hydroxylation, and CYP4A-catalyzed lauric acid 12-hydroxylation in the liver of rats fed the COS diets were observed compared with those rats fed the control diet. Immunoblot analyses of CYP proteins showed the same trend as with enzyme activities. Increased glutathione content in liver was found in rats fed the 1% COS diet. Increased hepatic NADPH: quinone oxidoreductase 1 (NQO1) activity was found in rats fed the COS diets. In kidneys, COS had little or no effect on CYP enzyme activities. However, increased GST activity was observed in rats fed the COS diets. Moreover, a higher UGT activity was found in rats fed the 1% COS diet. Our results indicate that COS may suppress hepatic CYP enzymes and induce phase II detoxifying reactions in the liver and kidneys of rats.

The collaborative experience of creating the National Capital Region Disease Surveillance Network.

The Johns Hopkins University Applied Physics Laboratory (JHU/APL) implemented state and district surveillance nodes in a central aggregated node in the National Capital Region (NCR). Within this network, de-identified health information is integrated with other indicator data and is made available to local and state health departments for enhanced disease surveillance. Aggregated data made available to the central node enable public health practitioners to observe abnormal behavior of health indicators spanning jurisdictions and view geographical spread of outbreaks across regions.Forming a steering committee, the NCR Enhanced Surveillance Operating Group (ESOG), was key to overcoming several data-sharing issues. The committee was composed of epidemiologists and key public health practitioners from the 3 jurisdictions. The ESOG facilitated early system development and signing of the cross-jurisdictional data-sharing agreement. This agreement was the first of its kind at the time and provided the legal foundation for sharing aggregated health information across state/district boundaries for electronic disease surveillance.Electronic surveillance system for the early notification of community-based epidemics provides NCR users with a comprehensive regional view to ascertain the spread of disease, estimate resource needs, and implement control measures. This article aims to describe the creation of the NCR Disease Surveillance Network as an exceptional example of cooperation and potential that exists for regional surveillance activities.

Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-kappaB pathway to reduce LPS-induced TNFalpha and NO expression.

Much recent research has demonstrated that honokiol, a phenolic compound originally isolated from Magnolia officinalis, has potent anticancer activities; however, the detailed molecular mechanism of its anti-inflammatory activity has not yet been fully addressed. In this study we demonstrated that honokiol inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha secretion in macrophages, without affecting the activity of the tumor necrosis factor-alpha converting enzyme. At the same time, honokiol not only inhibited nitric oxide expression in LPS-stimulated murine macrophages but also inhibited the LPS-induced phosphorylation of ERK1/2, JNK1/2, and p38. By means of confocal microscope analysis we demonstrated that phosphorylation and membrane translocation of protein kinase C-alpha, as well as NF-kappaB activation, were inhibited by honokiol in LPS-stimulated macrophages. Furthermore, it was found that honokiol neither antagonizes the binding of LPS to cells nor alters the cell surface expression of toll-like receptor 4 and CD14. Our current results have exhaustively described the anti-inflammatory properties of honokiol, which could lead to the possibility of its future pharmaceutical application in the realm of immunomodulation.

Utility of the ESSENCE Surveillance System in Monitoring the H1N1 Outbreak.

The Electronic Surveillance System for the Early Notification of Community-Based Epidemics (ESSENCE) enables health care practitioners to detect and monitor health indicators of public health importance. ESSENCE is used by public health departments in the National Capital Region (NCR); a cross-jurisdictional data sharing agreement has allowed cooperative health information sharing in the region since 2004. Emergency department visits for influenza-like illness (ILI) in the NCR from 2008 are compared to those of 2009. Important differences in the rates, timing, and demographic composition of ILI visits were found. By monitoring a regional surveillance system, public health practitioners had an increased ability to understand the magnitude and character of different ILI outbreaks. This increased ability provided crucial community-level information on which to base response and control measures for the novel 2009 H1N1 influenza outbreak. This report underscores the utility of automated surveillance systems in monitoring community-based outbreaks. There are several limitations in this study that are inherent with syndrome-based surveillance, including utilizing chief complaints versus confirmed laboratory data, discerning real disease versus those healthcare-seeking behaviors driven by panic, and reliance on visit counts versus visit rates.

INFOSHARE - An Information Sharing Tool for Public Health during the 2009 Presidential Inauguration and H1N1 Outbreak.

The 2009 Presidential Inauguration and H1N1 outbreak called for real-time electronic information-sharing and surveillance across multiple jurisdictions to better understand the health of migrating populations. The InfoShare web application proved to be an efficient tool for users to share disease surveillance information. During both high profile events, public health users shared information within a secure access-controlled website across regions in the U.S. and among agencies. Due to its flexible design, InfoShare was quickly modified from its 2009 Inauguration interface to an interface that supports H1N1 surveillance. Through discussions and post-use surveys, a majority of InfoShare users revealed that the tool had provided a valuable and needed function. InfoShare allowed individual jurisdictions to receive timely and useful information, which, when merged with neighboring jurisdictions, significantly enhanced situational awareness for better decision-making and improved public health outcomes.

Construction and validation of synthetic electronic medical records.

There is a current and pressing need for a test bed of electronic medical records (EMRs) to insure consistent development, validation and verification of public health related algorithms that operate on EMRs. However, access to full EMRs is limited and not generally available to the academic algorithm developers who support the public health community. This paper describes a set of algorithms that produce synthetic EMRs using real EMRs as a model. The algorithms were used to generate a pilot set of over 3000 synthetic EMRs that are currently available on CDC's Public Health grid. The properties of the synthetic EMRs were validated, both in the entire aggregate data set and for individual (synthetic) patients. We describe how the algorithms can be extended to produce records beyond the initial pilot data set.

Electronic medical record (EMR) utilization for public health surveillance.

INTRODUCTION: Public health surveillance systems need to be refined. We intend to use a generic approach for early identification of patients with severe influenza-like illness (ILI) by calculating a score that estimates a patients disease-severity. Accordingly, we built the Intelligent Severity Score Estimation Model (ISSEM), structured so that the inference process would reflect experts decision-making logic. Each patients disease-severity score is calculated from numbers of respiratory ICD9 encounters, and laboratory, radiologic, and prescription-therapeutic orders in the EMR. Other ISSEM components include chronic disease evidence, probability of immunodeficiency, and the providers general practice-behavior patterns. RESULTS: Sensitivity was determined from 200 randomly selected patients with upper- and lower-respiratory tract ILI; specificity, from 300 randomly selected patients with URI only. For different age groups, ISSEM sensitivity ranged between 90% and 95%; specificity was 72% to 84%. CONCLUSION: Our preliminary assessment of ISSEM performance demonstrated 93.5% sensitivity and 77.3% specificity across all age groups.