Prospects for Circumventing Aminoglycoside Kinase Mediated Antibiotic Resistance.

Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.

Front Cell Infect Microbiol. 2013; 3: 22
Shi K, Caldwell SJ, Fong DH, Berghuis AM

Aminoglycosides are a class of antibiotics with a broad spectrum of antimicrobial activity. Unfortunately, resistance in clinical isolates is pervasive, rendering many aminoglycosides ineffective. The most widely disseminated means of resistance to this class of antibiotics is inactivation of the drug by aminoglycoside-modifying enzymes (AMEs). There are two principal strategies to overcoming the effects of AMEs. The first approach involves the design of novel aminoglycosides that can evade modification. Although this strategy has yielded a number of superior aminoglycoside variants, their efficacy cannot be sustained in the long term. The second approach entails the development of molecules that interfere with the mechanism of AMEs such that the activity of aminoglycosides is preserved. Although such a molecule has yet to enter clinical development, the search for AME inhibitors has been greatly facilitated by the wealth of structural information amassed in recent years. In particular, aminoglycoside phosphotransferases or kinases (APHs) have been studied extensively and crystal structures of a number of APHs with diverse regiospecificity and substrate specificity have been elucidated. In this review, we present a comprehensive overview of the available APH structures and recent progress in APH inhibitor development, with a focus on the structure-guided strategies. HubMed – drug


Evolutionary dynamics of cancer in response to targeted combination therapy.

Elife. 2013; 2: e00747
Bozic I, Reiter JG, Allen B, Antal T, Chatterjee K, Shah P, Moon YS, Yaqubie A, Kelly N, Le DT, Lipson EJ, Chapman PB, Diaz LA, Vogelstein B, Nowak MA

In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI: HubMed – drug


Efficacy of a Culturally Based Parenting Intervention: Strengthening Open Communication Between Mexican-Heritage Parents and Adolescent Children.

J Soc Social Work Res. 2012 Dec 3; 3(4): 296-307
Williams LR, Ayers SL, Garvey MM, Marsiglia FF, Castro FG

This article presents the results of an initial efficacy trial of a parenting intervention, Familias: Preparando la Nueva Generación (FPNG), used to strengthen parenting practices, specifically, open family communication. Using community-based participatory research, including stakeholder involvement, the FPNG curriculum was developed, evaluated for feasibility, and revised to complement the classroom-based keepin’ itREAL youth substance-use prevention program. FPNG focuses on family influences that characterize Mexican-heritage youth and families, including the impact of acculturation. The 9 middle schools were block-randomized into 3 groups: parents and youth (PY), youth only (Y), and control (C) conditions. Parents of 7th grade youth (N = 393, 82.8% mothers) completed self-report surveys at baseline and immediately following the intervention. Structural equation model analyses confirmed that PY parents reported significantly greater levels of open family communication at the follow-up compared with Y parents; C parents were not significantly different from Y parents at follow-up. The inclusion of parents in adolescent-focused preventive interventions might increase the effect size of an original and efficacious youth prevention intervention. HubMed – drug


Coadministration of telaprevir and transcatheter arterial chemoembolization in hepatitis C virus-associated hepatocellular carcinoma.

World J Hepatol. 2013 Jun 27; 5(6): 332-335
Torres HA, Mahale P, Miller ED, Oo TH, Frenette C, Kaseb AO

The use of direct-acting antiviral agents (e.g., telaprevir, boceprevir) has improved response rates in patients with hepatitis C virus (HCV) genotype 1 infections. Substantial number of drug-drug interactions are anticipated with the use of telaprevir, a cytochrome P450 3A and P-glycoprotein substrate and inhibitor. Herein we describe a patient with HCV-associated hepatocellular carcinoma treated simultaneously with a telaprevir-containing regimen and localized chemotherapy (transcatheter arterial chemoembolization) with doxorubicin. No clinically relevant interactions or adverse events developed while on antiviral therapy. HubMed – drug