LD-Spline: Mapping SNPs on genotyping platforms to genomic regions using patterns of linkage disequilibrium

<p>Abstract</p> <p>Background</p> <p>Gene-centric analysis tools for genome-wide association study data are being developed both to annotate single locus statistics and to prioritize or group single nucleotide polymorphisms (SNPs) prior to analysis. These approaches require knowledge about the relationships between SNPs on a genotyping platform and genes in the human genome. SNPs in the genome can represent broader genomic regions via linkage disequilibrium (LD), and population-specific patterns of LD can be exploited to generate a data-driven map of SNPs to genes.</p> <p>Methods</p> <p>In this study, we implemented LD-Spline, a database routine that defines the genomic boundaries a particular SNP represents using linkage disequilibrium statistics from the International HapMap Project. We compared the LD-Spline haplotype block partitioning approach to that of the four gamete rule and the Gabriel et al. approach using simulated data; in addition, we processed two commonly used genome-wide association study platforms.</p> <p>Results</p> <p>We illustrate that LD-Spline performs comparably to the four-gamete rule and the Gabriel et al. approach; however as a SNP-centric approach LD-Spline has the added benefit of systematically identifying a genomic boundary for each SNP, where the global block partitioning approaches may falter due to sampling variation in LD statistics.</p> <p>Conclusion</p> <p>LD-Spline is an integrated database routine that quickly and effectively defines the genomic region marked by a SNP using linkage disequilibrium, with a SNP-centric block definition algorithm.</p

Life-Long Radar Tracking of Bumblebees

This work was supported by European Research Council Advanced Grant no. 339347

Anti-emetic drugs in oncology: pharmacology and individualization by pharmacogenetics

Objective Nausea and vomiting are the most distressful side effects of cytotoxic drugs in cancer patients. Antiemetics are commonly used to reduce these side effects. However, the current antiemetic efficacy is about 70–80% in patients treated with highly-emetogenic cytotoxic drugs. One of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins which play a role in metabolism, transport and receptors related to antiemetic drugs. Aim of this review was to describe the pharmacology and pharmacogenetic concepts of of antiemetics in oncology. Method Pharmacogenetic and pharmacology studies of antiemetics in oncology published between January 1997 and February 2010 were searched in PubMed. Furthermore, related textbooks were also used for exploring the pharmacology of antiemetic drugs. The antiemetic drugs which were searched were the 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs), dopamine antagonists, corticosteroids, benzodiazepines, cannabinoids, antihistamines and neurokinin-1 antagonists. Result The 5-HT3RAs are widely used in highly emetogenic chemotherapy in combination with dexamethasone and a neurokinin-1 antagonist, especially in acute phase. However, the dopamine antagonists and benzodiazepines were found more appropriate for use in breakthrough and anticipatory symptoms or in preventing the delayed phase of chemotherapy induced nausea and vomiting. The use of cannabinoids and antihistamines need further investigation. Only six articles on pharmacogenetics of the 5-HT3RAs in highly emetogenic chemotherapy are published. Specifically, these studies investigated the association of the efficacy of 5-HT3RAs and variants in the multi drug resistance 1 (MDR1) gene, 5-HT3A,B and C receptor genes and CYP2D6 gene. The pharmacogenetic studies of the other antiemetics were not found in this review. Conclusion It is concluded that pharmacogenetic studies with antiemetics are sparse. It is too early to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice: confirmation of early findings is required

Pain Management in Patients with Cancer: Focus on Opioid Analgesics

Cancer pain is generally treated with pharmacological measures, relying on using opioids alone or in combination with adjuvant analgesics. Weak opioids are used for mild-to-moderate pain as monotherapy or in a combination with nonopioids. For patients with moderate-to-severe pain, strong opioids are recommended as initial therapy rather than beginning treatment with weak opioids. Adjunctive therapy plays an important role in the treatment of cancer pain not fully responsive to opioids administered alone (ie, neuropathic, bone, and visceral colicky pain). Supportive drugs should be used wisely to prevent and treat opioids’ adverse effects. Understanding the pharmacokinetics, pharmacodynamics, interactions, and cautions with commonly used opioids can help determine appropriate opioid selection for individual cancer patients

Pain in the cancer patient : different pain characteristics CHANGE pharmacological treatment requirements

Peer reviewe

Safety of oral methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain

Richard L Rauck,1 Neal E Slatkin,2,3 Nancy Stambler,4 Robert J Israel3 1Carolinas Pain Institute, Winston-Salem, NC, USA; 2School of Medicine, University of California Riverside, Riverside, CA, USA; 3Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA; 4Clinical Research, Progenics Pharmaceuticals, New York, NY, USA Purpose: Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study. Methods: Adults (n=803) with chronic noncancer pain for &ge;2 months and confirmed OIC while receiving opioid doses &ge;50 mg morphine equivalent per day for &ge;14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores. Results: TEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days, P=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal. Conclusion: Oral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal. Keywords: analgesia, &micro;-opioid-receptor antagonist, nonmalignant, safet