Effects of anthropogenic and demographic factors on patterns of parasitism in African small mammal communities

SUMMARYHabitat disturbance often results in alterations in community structure of small mammals. Additionally, the parasites harboured by these small mammals may be impacted by environmental changes or indirectly affected by changes in available hosts. To improve our understanding of this interplay, we examined the patterns of parasitism in small mammal communities from a variety of habitats in forested Uganda. Small mammals were collected from areas experiencing variable habitat disturbance, host density and species richness. The analysis focused on 3 most abundant rodent species, Lophuromys aquilus, Praomys jacksoni and Hylomyscus stella, and a diverse group of parasites they harbour. The impact of various habitat and host community factors on parasite prevalence was examined using linear regression and Spearman's rank-order correlation. We further investigated the parasite communities associated with each individual using correspondence analysis. We determined that, parasite prevalence and richness may be occasionally influenced by community and habitat factors, but taxonomy is a driving force in influencing the parasite community harboured by an individual host. Ultimately, applying general principles across a broad range of disturbance levels and diverse host communities needs to be approached with caution in complex communities.</jats:p

Estrogen Receptor α and Aromatase Polymorphisms Affect Risk, Prognosis, and Therapeutic Outcome in Men with Castration-Resistant Prostate Cancer Treated with Docetaxel-Based Therapy

Abstract Context Reactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC). Objective We hypothesized that polymorphisms in estrogen synthesis and estrogen targets (i.e., CYP19 and ERα) would be linked to interindividual variation in CRPC risk, docetaxel response, and overall survival (OS) in men with CRPC. Materials and Methods Patients with CRPC (n = 115) treated with docetaxel, single-agent thalidomide (n = 42), or healthy controls (n = 289) were genotyped for the CYP19 R264C (rs700519) and the ERα PvuII T&amp;gt; C (rs2234693) and XbaI A&amp;gt; G (rs9340799) polymorphisms. Results Patients carrying two copies of ERα polymorphisms had shorter progression-free survival on docetaxel than other patients (median survival difference ≥3.1 months; P ≤ 0.036). When the analysis was limited to nonobese patients, the relationship between the ERα XbaI A&amp;gt; G polymorphism and PFS improved (median survival difference = 3.5 months; P = 0.0078). The CYP19 R264C variant was related to the duration of survival after docetaxel in patients who were &amp;gt; 70 years old (median survival difference = 10.6 months; P = 0.041). Both ERα polymorphisms were also associated with increases in CRPC risk [P ≤ 0.032; double variants vs. wild-type odds ratio (OR) ≥ 2.6], and the association with the ERα PvuII T&amp;gt; C also improved in those men who were &amp;lt; 70 years old (P = 0.0073; OR = 3.0). Conclusions This study demonstrates that estrogen-related genetic variation affects docetaxel clinical response and that this relationship is dependent on age and body-type in men with CRPC. Moreover, this study suggests ERα polymorphisms confer risk of developing prostate cancer, especially in men under 70 years of age. </jats:sec

A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform

3580 Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p&lt;0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. No significant financial relationships to disclose. </jats:p

Estrogen Receptor α and Aromatase Polymorphisms Affect Risk, Prognosis, and Therapeutic Outcome in Men with Castration-Resistant Prostate Cancer Treated with Docetaxel-Based Therapy

ERα and CYP19 polymorphisms affect the therapeutic outcome of docetaxel in patients with castrationresistant prostate cancer (CRPC) and are associated with CRPC risk