Barriers to colorectal cancer screening among American Indian men aged 50 or older, Kansas and Missouri, 2006-2008

American Indian (AI) men have some of the highest rates of colorectal cancer (CRC) in the United States but among the lowest screening rates. Our goal was to better understand awareness and discourse about colorectal cancer in a heterogeneous group of AI men in the Midwestern United States. Focus groups were conducted with AI men (N = 29); data were analyzed using a community-participatory approach to qualitative text analysis. Several themes were identified regarding knowledge, knowledge sources, and barriers to and facilitators of screening. Men in the study felt that awareness about colorectal cancer was low, and people were interested in learning more. Education strategies need to be culturally relevant and specific

Internet Use for Health Information among American Indians: Facilitators and Inhibitors

Our research team explored Internet use among a heterogeneous American Indian (AI) population to determine Internet use in relation to health information seeking behaviors. Participants examined an AI culturally-tailored tobacco website as an example to explain what they wanted in an AI Internet health site. Using community-based participatory research, we conducted 10 focus groups with non-college AI men and women (N=96), stratified by age (18-29, 30-49, and 50 and over) to better understand their perceptions of Internet use and health information needs. We found that Internet use varied greatly among all strata. Participants referenced WebMD© more than any other website, but participants were not pleased with the design and navigation. When examining the sample website, participants across strata stressed that recreational and traditional tobacco use should be discussed. Participants in all strata desired a simple website design with easy to read text accompanied by images. In order to gain and maintain cultural respect, participants stated that web designers should be aware that some images hold cultural meaning, particularly tobacco. Baseline data are needed for AI’s use of the Internet to obtain health information; this research is helpful to address health inequalities among AI, particularly access to web-based health information

Influence of Dietary Substances on Intestinal Drug Metabolism and Transport

Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of dietary substances on drug disposition and response. Some dietary substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3A-mediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitro-in vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as dietary substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given dietary substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-dietary substance interactions appropriately

Evaluation of the Effects of Repeat-Dose Dabrafenib on the Single-Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate)

Dabrafenib; Drug interaction; PharmacokineticsDabrafenib; Interacción de fármacos; FarmacocinéticaDabrafenib; Interacció de fàrmacs; FarmacocinèticaDabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation–positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open-label, fixed-sequence study in patients with BRAF V600 mutation–positive tumors. Repeat dabrafenib dosing resulted in a 2.56-fold increase in rosuvastatin maximum observed concentration (Cmax), an earlier time to Cmax, but only a 7% increase in area under the concentration-time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax. No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase.This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015

Ensuring Healthy American Indian Generations for Tomorrow through Safe and Healthy Indoor Environments

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.American Indians (AI) have the highest rate of severe physical housing problems in the U.S. (3.9%). Little information exists about the environmental hazards in AI homes. The purposes of this paper are to discuss challenges that were encountered when recruiting AI for a home-and employment-based environmental health assessments, highlight major successes, and propose recommendations for future indoor environmental health studies. The Center for American Indian Community Health (CAICH) and Children’s Mercy Hospital’s Center for Environmental Health and Allergy and Immunology Research Lab collaborated to provide educational sessions and healthy home assessments for AI. Through educational trainings, more than 240 AI were trained on the primary causes of health problems in homes. A total of 72 homes and places of employment were assessed by AI environmental health specialists. The top three categories with the most concerns observed in the homes/places of employment were allergens/dust (98%), safety/injury (89%) and chemical exposure (82%). While some information on smoking inside the home was collected, these numbers may have been underreported due to stigma. This was CAICH’s first endeavor in environmental health and although challenges arose, many more successes were achieved

Internet All Nation Breath of life (I-ANBL) a Tribal College Student Engaged Development of an Internet-based Smoking Cessation Intervention

Background: Compared to non-Hispanic white college students, American Indian (AI) tribal college students have the highest smoking prevalence in the U.S. (~34%). Culturally-tailored smoking cessation programs have proven to be successful in reducing smoking rates but may require new methods to reach college students. Currently, there is little documentation on the development and success of Internet-based smoking interventions for AI tribal college students. Objectives: To develop an Internet-based smoking cessation program (Internet-All Nations Breath of Life or I-ANBL) with tribal college students. Methods: We conducted six focus groups (n=41) at a tribal college. Focus groups included tribal college students who smoked and groups were stratified by sex. Transcripts were analyzed using insider and outsider perspectives. After analysis, an Internet-based smoking cessation program was developed, based on insight gained. Results: Numerous suggestions for creating the program were offered. There was consensus on the need for a variety of visuals including cultural images, videos, and interactive content. The students also suggested the integration of familiar platforms such as FacebookTM. Conclusion: When culturally tailoring a web-based smoking cessation program for tribal college students, it is important to incorporate cultural aspects and recognize gender differences. One important aspect is to recognize that for many AI, tobacco is a sacred plant and images of tobacco should be respectful. Now that this intervention has been developed, next we will test it for efficacy in a randomized controlled trial. Keywords: American Indians, tribal college, tobacco, program development, smoking cessation, community-based participatory researc

A Modified Grapefruit Juice Eliminates Two Compound Classes as Major Mediators of the Grapefruit Juice-Fexofenadine Interaction: An In Vitro-In Vivo “Connect”: The Journal of Clinical Pharmacology

The grapefruit juice-fexofenadine interaction involves inhibition of intestinal organic anion transporting polypeptide (OATP)-mediated uptake. Only naringin has been shown clinically to inhibit intestinal OATP; other constituents have not been evaluated. The effects of a modified grapefruit juice devoid of furanocoumarins (~99%) and polymethoxyflavones (~90%) on fexofenadine disposition were compared to effects of the original juice. Extracts of both juices inhibited estrone 3-sulfate and fexofenadine uptake by similar extents in OATP-transfected cells (~50% and ~25%, respectively). Healthy volunteers (n=18) were administered fexofenadine (120 mg) with water, grapefruit juice, or modified grapefruit juice (240 ml) by randomized, three-way crossover design. Compared to water, both juices decreased fexofenadine geometric mean AUC and Cmax by ~25% (p≤0.008 and p≤0.011, respectively), with no effect on terminal half-life (p=0.11). Similar effects by both juices on fexofenadine pharmacokinetics indicate furanocoumarins and polymethoxyflavones are not major mediators of the grapefruit juice-fexofenadine interaction

Structure of the γ-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases.

Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-D-glutamyl-L-diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-γ-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and γ-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-alanine-γ-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site

The structure of BVU2987 from Bacteroides vulgatus reveals a superfamily of bacterial periplasmic proteins with possible inhibitory function.

Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a β-lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to β-lactamase inhibitor protein, PepSY and SmpA_OmlA proteins and hence are likely to function as inhibitory proteins

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes

PURPOSE: Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. EXPERIMENTAL DESIGN: A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS). RESULTS: Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R-NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P \u3c 0.0001). CONCLUSIONS: This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset