The Role of Active Brown Adipose Tissue in Patients With Pheochromocytoma or Paraganglioma.

Objectives: Metabolically-active brown adipose tissue (aBAT) is a common finding on fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in patients with pheochromocytoma or paraganglioma (PPGL). In addition to its clinical significance, we aimed to explore the prevalence of this finding on FDG-PET imaging in patients with PPGL.

Methods: We conducted a systematic review and meta-analysis of prospective and retrospective studies.

Influx transporter variants as predictors of cancer chemotherapy-induced toxicity: systematic review and meta-analysis.

Aim: Chemotherapeutic agents have been shown to increase lung patient survival, however their use may be limited by their serious adverse effects. We aimed to assess int impact of pharmacogenetic variation of influx transporters on inter-individual patient variation in adverse drug reactions.

Patients & Methods: We conducted a meta-analysis and systemic review and identified 16 publications, totaling 1510 patients, to be eligible for review.

Efflux transporter variants as predictors of drug toxicity in lung cancer patients: systematic review and meta-analysis.

Unlabelled: Chemotherapeutic drugs are underutilized in lung cancer management due in part to serious adverse drug reactions (ADRs).

Aim: With studies revealing an association between interindividual patient ADR variation and efflux transporter variants, we carried out a meta-analysis and systemic review, in order to highlight current knowledge regarding the strength of association between efflux transporter SNPs variants and chemotherapeutic-drug induced ADRs.

Materials & Methods: Papers were sourced from MEDLINE, Cochrane Library, CINHL, EMBASE, Web of Knowledge, Scopus.

Clinical Perspectives on Targeting Therapies for Personalized Medicine.

Expected benefits from new technology include more efficient patient selection for clinical trials, more cost-effective treatment pathways for patients and health services and a more profitable accelerated approach for drug developers. Regulatory authorities expect the pharmaceutical and biotechnology industries to accelerate their development of companion diagnostics and companion therapeutics toward the goal of safer and more effective personalized medicine, and expect health services to fund and prescribers to adopt these new therapeutic technologies. This review discusses the importance of a range of new approaches to developing new and reprofiled medicines to treat common and serious diseases, and rare diseases: new network pharmacology approaches, adaptive trial designs with enriched populations more likely to respond safely to treatment, as assessed by companion diagnostics for response and toxicity risk and use of "real world" data.

The clastogenicity of 4NQO is cell-type dependent and linked to cytotoxicity, length of exposure and p53 proficiency.

4-Nitroquinoline 1-oxide (4NQO) is used as a positive control in various genotoxicity assays because of its known mutagenic and carcinogenic properties. The chemical is converted into 4-hydroxyaminoquinoline 1-oxide and gives rise to three main DNA adducts, N-(deoxyguanosin-8-yl)-4AQO, 3-(desoxyguanosin-N (2)-yl)-4AQO and 3-(deoxyadenosin-N (6)-yl)-4AQO. This study was designed to assess the shape of the dose-response curve at low concentrations of 4NQO in three human lymphoblastoid cell lines, MCL-5, AHH-1 and TK6 as well as the mouse lymphoma L5178Y cell line in vitro.

Real-time reverse-transcription polymerase chain reaction: technical considerations for gene expression analysis.

The reverse transcription - polymerase chain reaction (RT-PCR) is a sensitive technique for the quantification of steady-state mRNA levels, particularly in samples with limited quantities of extracted RNA, or for analysis of low level transcripts. The procedure amplifies defined mRNA transcripts by taking advantage of retroviral enzymes with reverse transcriptase (RT) activity, coupled to PCR. The resultant PCR product concentration is directly proportional to the initial starting quantity of mRNA, therefore allowing quantification of gene expression by incorporation of a fluorescence detector for the appropriate amplicons.

N-methylpurine DNA glycosylase plays a pivotal role in the threshold response of ethyl methanesulfonate-induced chromosome damage.

Genotoxic tolerance to low-level exposure of monofunctional alkylating agents is compound specific, with the mechanism pertaining to alkyl-induced genotoxic threshold response as yet unknown. N-methylpurine DNA glycosylase (MPG), an initiator glycosylase of the base excision repair (BER) pathway, typically repairs alkyl-induced DNA adducts, many of which are associated with genomic instability and tumorigenic risk. Here we demonstrate the involvement of MPG in modulating the genotoxic threshold response induced by the Sn2 alkylating agent ethyl methanesulfonate (EMS) and not the Sn1 alkylating agent N-ethyl-N-nitrosourea (ENU) in human lymphoblastoid cells and suggest the lack of N7-ethylguanine adduct repair as a key factor attributable to an observed increase in EMS-induced chromosome damage.

Genotoxic thresholds, DNA repair, and susceptibility in human populations.

It has been long assumed that DNA damage is induced in a linear manner with respect to the dose of a direct acting genotoxin. Thus, it is implied that direct acting genotoxic agents induce DNA damage at even the lowest of concentrations and that no "safe" dose range exists. The linear (non-threshold) paradigm has led to the one-hit model being developed.

Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter.

Folates are essential for nucleic acid synthesis and are particularly required in rapidly proliferating tissues, such as intestinal epithelium and hemopoietic cells. Availability of dietary folates is determined by their absorption across the intestinal epithelium, mediated by the proton-coupled folate transporter (PCFT) at the apical enterocyte membranes. Whereas transport properties of PCFT are well characterized, regulation of PCFT gene expression remains less elucidated.

Non-linear dose-response of DNA-reactive genotoxins: recommendations for data analysis.

Until recently, there has only been a limited amount of data available on the kinetics of mutation induction in the low dose region of exposure. In our publication Doak et al. [S.

Pharmacogenetics of OATP (SLC21/SLCO), OAT and OCT (SLC22) and PEPT (SLC15) transporters in the intestine, liver and kidney.

The role of carrier-mediated transport in determining the pharmacokinetics of drugs has become increasingly evident with the discovery of genetic variants that affect expression and/or function of a given drug transporter. Drug transporters are expressed at numerous epithelial barriers, such as intestinal epithelial cells, hepatocytes, renal tubular cells and at the blood-brain barrier. Several recent studies have associated alterations in substrate uptake with the presence of SNPs.