Thiopurine S -methyltransferase polymorphisms: efficient screening method for patients considering taking thiopurine drugs

Objective: More than 11% of the Caucasian population are heterozygous or homozygous carriers of thiopurine S-methyltransferase (TPMT) mutants and are at risk for toxic side effects when treated with thiopurine drugs. Therefore, screening for TPMT polymorphisms in a patient prior to prescribing these agents is recommended. The goal of this study was to determine a cut-off concentration of the TPMT activity assay beyond which genotyping of the TPMT gene should be performed. Methods: The TPMT activity of 240 unrelated Caucasian subjects was measured using high-performance liquid chromatography. Genotyping for the most frequent allelic variants, TPMT*2, *3A, *3B, *3C and *7 was performed by LightCycler technology and sequencing. Results: The inter-individual TPMT activity showed a range from 23nmol MTG/g*Hb*h−1 to 97nmol MTG/g*Hb*h−1 with a median of 56nmol MTG/g*Hb*h−1. Using a cut-off concentration of 45.5nmol MTG/g*Hb*h−1, a test sensitivity of 100% and a specificity of 89% were reached for heterozygous carriers of a TPMT mutation. We identified 1 carrier of TPMT*2, 14 carriers of TPMT*3A and 3 carriers of TPMT*3C, resulting in a TPMT heterozygosity prevalence of 7.5%. Conclusions: This study defines the cut-off value for the TPMT phenotyping assay at 45.5nmol/g*Hb*h−1, beyond which additional genotyping elucidates the individual risk for drug therapy. Using this cut-off concentration, the number of genotyping assays could be reduced by about 60

Association Between Gabapentin Receipt for Any Indication and Alcohol Use Disorders Identification Test-Consumption Scores Among Clinical Subpopulations With and Without Alcohol Use Disorder.

BACKGROUND: Current medications for alcohol use disorder (AUD) have limited efficacy and utilization. Some clinical trials have shown efficacy for gabapentin among treatment-seeking individuals. The impact of gabapentin on alcohol consumption in a more general sample remains unknown. METHODS: We identified patients prescribed gabapentin for ≥180 consecutive days for any clinical indication other than substance use treatment between 2009 and 2015 in the Veterans Aging Cohort Study. We propensity-score matched each gabapentin-exposed patient with up to 5 unexposed patients. Multivariable difference-in-difference (DiD) linear regression models estimated the differential change in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores during follow-up between exposed and unexposed patients, by baseline level of alcohol consumption and daily gabapentin dose. Analyses were stratified by AUD history. Clinically meaningful changes were a priori considered a DiD ≥1 point. RESULTS: Among patients with AUD, AUDIT-C scores decreased 0.39 points (95% confidence interval [CI] 0.05, 0.73) more among exposed than unexposed patients (p < 0.03). Potentially clinically meaningful differences were observed among those with AUD and exposed to ≥1,500 mg/d (DiD 0.77, 95% CI 0.15, 1.38, p < 0.02). No statistically significant effects were found among patients with AUD at doses lower than 1,500 mg/d or baseline AUDIT-C ≥4. Among patients without AUD, we found no overall difference in changes in AUDIT-C scores, nor in analyses stratified by baseline level of alcohol consumption. CONCLUSIONS: Patients exposed to doses of gabapentin consistent with those used in clinical trials, particularly those with AUD, experienced a greater decrease in AUDIT-C scores than matched unexposed patients

2,2':6',2''-Terpyridine-functionalized redox-responsive hydrogels as a platform for multi responsive amphiphilic polymer membranes

Nanophase-separated amphiphilic polymer co-networks are ideally suited as responsive membranes due to their stable co-continuous structure. Their functionalization with redox-responsive 2,2′:6′,2′′-terpyridine–metal complexes and light-responsive spiropyran derivatives leads to a novel material with tunable optical, redox and permeability properties. The versatility of the system in complexing various metal ions, such as cobalt or iron at different concentrations, results in a perfect monitoring over the degree of crosslinking of the hydrophilic poly(2-hydroxyethyl acrylate) channels. The reversibility of the complexation, the redox state of the metal and the isomerization to the merocyanine form upon UV illumination was evidenced by cyclic voltammetry, UV-Vis and permeability measurements under sequential conditions. Thus, the membrane provides light and redox addressable functionalities due to its adjustable and mechanically stable hydrogel network

ABCC1: a gateway for pharmacological compounds to the ischaemic brain

By preventing access of drugs to the CNS, the blood-brain barrier hampers developments in brain pharmacotherapy. Strong efforts are currently being made to identify drugs that accumulate more efficaciously in ischaemic brain tissue. We identified an ATP-binding cassette (ABC) transporter, ABCC1, which is expressed on the abluminal surface of the brain capillary endothelium and mildly downregulated in response to focal cerebral ischaemia, induced by intraluminal middle cerebral artery occlusion. In biodistribution studies we show that ABCC1 promotes the accumulation of known neuroprotective and neurotoxic compounds in the ischaemic and non-ischaemic brain, ABCC1 deactivation reducing tissue concentrations by up to two orders of magnitude. As such, ABCC1's expression and functionality in the brain differs from the liver, spleen and testis, where ABCC1 is strongly expressed on parenchymal cells, resulting -- in case of liver and testis -- in directed transport from the tissue into the blood. After focal cerebral ischaemia, ABCC1 deactivation abolished the efficacy of both neuroprotective and neurotoxic compounds. Our data indicate that ABCC1 acts as gateway for pharmacological compounds to the stroke brain. We suggest that the tailoring of compounds binding to abluminal but not luminal ABC transporters may facilitate stroke pharmacotherap

Interdisciplinary evidence-based recommendations for the follow-up of testicular cancer patients: a joint effort

Detailed recommendations for the treatment of testicular cancer exist and due to the stringent application of the standard therapies, most patients can nowadays be cured. Moreover in the treatment of early stage disease, active surveillance is now a cornerstone of treatment. Hence there is a clear need for recommendations regarding the long term follow-up of these young patients. These have to be safe, feasible and the intensity of procedures have to reflect the known risk of recurrence. Different proposals have been published but they differ widely especially in terms of frequency and modality of imaging. In the last few years, new evidence has become available regarding the relapse pattern of different disease stages of testicular cancer, the use of imaging in follow-up and the risks of excessive radiation due to imaging, in particular with CT scans. In this article, an interdisciplinary, multinational working group has reviewed the evidence and based on this has formulated practical recommendations for the follow-up of patients with testicular cancer

Conservation and economic benefits of a road around the Serengeti

No abstract available

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Pharmacogenomics driven decision support prototype with machine learning: A framework for improving patient care

Introduction: A growing number of healthcare providers make complex treatment decisions guided by electronic health record (EHR) software interfaces. Many interfaces integrate multiple sources of data (e.g., labs, pharmacy, diagnoses) successfully, though relatively few have incorporated genetic data. Method: This study utilizes informatics methods with predictive modeling to create and validate algorithms to enable informed pharmacogenomic decision-making at the point of care in near real-time. The proposed framework integrates EHR and genetic data relevant to the patient's current medications including decision support mechanisms based on predictive modeling. We created a prototype with EHR and linked genetic data from the Department of Veterans Affairs (VA), the largest integrated healthcare system in the US. The EHR data included diagnoses, medication fills, and outpatient clinic visits for 2,600 people with HIV and matched uninfected controls linked to prototypic genetic data (variations in single or multiple positions in the DNA sequence). We then mapped the medications that patients were prescribed to medications defined in the drug-gene interaction mapping of the Clinical Pharmacogenomics Implementation Consortium's (CPIC) level A (i.e., sufficient evidence for at least one prescribing action) guidelines that predict adverse events. CPIC is a National Institute of Health funded group of experts who develop evidence based pharmacogenomic guidelines. Preventable adverse events (PAE) can be defined as a harmful outcome from an intervention that could have been prevented. For this study, we focused on potential PAEs resulting from a medication-gene interaction. Results: The final model showed AUC scores of 0.972 with an F1 score of 0.97 with genetic data as compared to 0.766 and 0.73 respectively, without genetic data integration. Discussion: Over 98% of people in the cohort were on at least one medication with CPIC level a guideline in their lifetime. We compared predictive power of machine learning models to detect a PAE between five modeling methods: Random Forest, Support Vector Machine (SVM), Extreme Gradient Boosting (XGBoost), K Nearest neighbors (KNN), and Decision Tree. We found that XGBoost performed best for the prototype when genetic data was added to the framework and improved prediction of PAE. We compared area under the curve (AUC) between the models in the testing dataset

Work-Unit Absenteeism: Effects of Satisfaction, Commitment, Labor Market Conditions, and Time

Prior research is limited in explaining absenteeism at the unit level and over time. We developed and tested a model of unit-level absenteeism using five waves of data collected over six years from 115 work units in a large state agency. Unit-level job satisfaction, organizational commitment, and local unemployment were modeled as time-varying predictors of absenteeism. Shared satisfaction and commitment interacted in predicting absenteeism but were not related to the rate of change in absenteeism over time. Unit-level satisfaction and commitment were more strongly related to absenteeism when units were located in areas with plentiful job alternatives

Multimodality Treatment with Conventional Transcatheter Arterial Chemoembolization and Radiofrequency Ablation for Unresectable Hepatocellular Carcinoma

Background/Aims: To evaluate the efficacy of multimodality treatment consisting of conventional transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in patients with non-resectable and non-ablatable hepatocellular carcinoma (HCC). Methods: In this retrospective study, 85 consecutive patients with HCC (59 solitary, 29 multifocal HCC) received TACE followed by RFA between 2001 and 2010. The mean number of tumors per patient was 1.6 +/- 0.7 with a mean size of 3.0 +/- 0.9 cm. Both local efficacy and patient survival were evaluated. Results: Of 120 treated HCCs, 99 (82.5%) showed a complete response (CR), while in 21 HCCs (17.5%) a partial response was depicted. Patients with solitary HCC revealed CR in 91% (51/56); in patients with multifocal HCC (n = 29) CR was achieved in 75% (48 of 64 HCCs). The median survival for all patients was 25.5 months. The 1-, 2-, 3- and 5-year survival rates were 84.6, 58.7, 37.6 and 14.6%, respectively. Statistical analysis revealed a significant difference in survival between Barcelona Clinic Liver Cancer (BCLC) A (73.4 months) and B (50.3 months) patients, while analyses failed to show a difference for Child-Pugh score, Cancer of Liver Italian Program (CLIP) score and tumor distribution pattern. Conclusion: TACE combined with RFA provides an effective treatment approach with high local tumor control rates and promising survival data, especially for BCLC A patients. Randomized trials are needed to compare this multimodality approach with a single modality approach for early-stage HCC. Copyright (C) 2011 S. Karger AG, Base