High-quality biocompatible magnetic iron oxide (Fe3O4) nanocrystals were developed through a ligand exchange process of hydrophobically capped nanocrystals with hydrophilic molecules. By simple modulation of the nanocrystal surface ligand charge properties, we have been able to prepare magnetic nanocrystals with excellent intracellular labeling capabilities that efficiently label a variety of cell types without the need for additional transport facilitating agents. The excellent intracellular labeling capability of the newly developed cationic WSIO has further led to successful MRI monitoring of the migration of neural stem cells in rat spinal cord. The magnetic nanocrystals developed here have great potential in applications for labeling of various cell types and also the monitoring of cell-based medical treatments and cancer metastasis.

Objective The goal of this study was to determine the effect of a genetic variant in the organic cation transporter (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the anti-diabetic drug, metformin. Methods The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [fourteen homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited into this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both groups. Results We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics were characterized in twenty-three healthy volunteers of Caucasian and African American ancestries. We observed that the renal clearance (CLR) and the net secretion (SrCLR) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (p<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CLR and SrCLR of metformin (p<0.01). Conclusion We conclude that genetic variation in OCT2 plays an important role in the CLR and SrCLR of metformin in healthy volunteers.

Synthesis of a size series of colloidal ZnTe/ZnSe (core/shell) quantum dots (QDs) is reported. Because of the unique Type-II characters, their emission can range over an extended wavelength regime, showing photoluminescence (PL) from blue to amber. The PL lifetime measures as long as 77 ns, which clearly indicates the Type-II characteristics. ZnTe/ZnSe (Core/Shell) QDs can be further passivated by ZnS layers, rendered in water, while preserving the optical and chemical stabilities and thus proved their potentials toward “nontoxic” biological or medical applications that are free from concerns regarding heavy-metal leakage. ZnTe/ZnSe Type-II QD/polymer hybrid organic solar cells are also showcased, promising environmentally friendly photovoltaic devices. ZnTe/ZnSe Type-II QD incorporated photovoltaic devices show 11 times higher power conversion efficiency, when compared to that of the control ZnSe QD devices. This results from the Type-II characteristic broad QD absorption up to extended wavelengths and the spatially separated Type-II excitons, which can enhance the carrier extractions. We believe that ZnTe/ZnSe-based Type-II band engineering can open many new possibilities as exploiting the safe material choice.

Unlike tumor biopsies that can be constrained by problems such as sampling bias, circulating tumor cells (CTCs) are regarded as the “liquid biopsy” of the tumor, providing convenient access to all disease sites, including primary tumor and fatal metastases. Although enumerating CTCs is of prognostic significance in solid tumors, it is conceivable that performing molecular and functional analyses on CTCs will reveal much significant insight into tumor biology to guide proper therapeutic intervention. We developed the Thermoresponsive NanoVelcro CTC purification system that can be digitally programmed to achieve an optimal performance for purifying CTCs from non-small cell lung cancer (NSCLC) patients. The performance of this unique CTC purification system was optimized by systematically modulating surface chemistry, flow rates, and heating/cooling cycles. By applying a physiologically endurable stimulation (i.e., temperature between 4 and 37 °C), the mild operational parameters allow minimum disruption to CTCs’ viability and molecular integrity. Subsequently, we were able to successfully demonstrate culture expansion and mutational analysis of the CTCs purified by this CTC purification system. Most excitingly, we adopted the combined use of the Thermoresponsive NanoVelcro system with downstream mutational analysis to monitor the disease evolution of an index NSCLC patient, highlighting its translational value in managing NSCLC.

Aberrant membrane transport caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with a wide spectrum of respiratory and digestive diseases as well as cystic fibrosis. Using a gene scanning method, we found 11 polymorphisms and mutations of the CFTR gene in the Korean population. Individual variants at these sites were analyzed by conventional DNA screening in 117 control and 75 patients having bronchiectasis or chronic pancreatitis. In a haplotype determination based on a Bayesian algorithm, 15 haplotypes were assembled in the 192 individuals tested. Several haplotypes, especially with Q1352H, IVS8 T5, and E217G, were found to have disease associations in a case-control study. Notably, a common polymorphism of M470V appears to affect the intensity of the disease association. Among the two haplotypes having IVS8 T5, the T5-V470 haplotype showed higher disease association than the T5-M470 haplotype. In addition, a Q1352H mutation found in a V470 background showed the strongest disease association. The physiological significances of the identified mutations were rigorously analyzed. Non-synonymous E217G and Q1352H mutations in the M470 background caused a 60-80% reduction in CFTR-dependent Cl(-) currents and HCO3(-) -transport activities. Surprisingly, the additional M470V polymorphic variant with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. These findings provide the first evidence on the importance of CFTR mutations in the Asian population. Importantly, the results also reveal that interactions between multiple genetic variants in cis affect the final function of the gene products.

Organic cation transporter 1 (OCT1; SLC22A1) seems to play a role in the efficacy and disposition of the widely used antidiabetic drug metformin. Genetic variants in OCT1 have been identified largely in European populations. Metformin is increasingly being used in Asian populations where the incidence of type 2 diabetes (T2D) is on the rise. The goal of this study is to identify genetic variants of OCT1 in Chinese and Japanese populations, which may potentially modulate response to metformin. We used recent data from the 1000 Genomes Project (Chinese and Japanese) and direct sequencing of selected amplicons of OCT1 in 66 DNA samples from Japanese patients with T2D. A total of six nonsynonymous variants were identified. Three of them (Q97K, P117L, and R206C) had not been functionally characterized previously and had allele frequencies of 0.017, 0.023 and 0.008, respectively. The uptake of metformin in cells expressing Q97K, P117L, and R206C was significantly reduced relative to the OCT1 reference (62 Ϯ 4.3, 55 Ϯ 6.8, and 22 Ϯ 1.5% for Q97K, P117L, and R206C, respectively). Kinetic studies indicated that P117L and R206C exhibited a reduced V max , whereas Q97K showed an increased K m . The green fluorescent protein (GFP)-tagged Q97K and P117L variants localized to the plasma membrane, whereas the GFP-tagged R206C was retained mainly in the endoplasmic reticulum. Replacement of the highly conserved R206 with different amino acids modulated the subcellular localization and function of the transporter. This study suggests that nonsynonymous variants of OCT1 in Chinese and Japanese populations may affect the differential response to metformin.

Objectives CYP3A4 receives electrons from P450 oxidoreductase (POR) to metabolize about 50% of clinically used drugs. There is substantial inter-individual variation in CYP3A4 catalytic activity that is not explained by CYP3A4 genetic variants. CYP3A4 is flexible and distensible, permitting it to accommodate substrates varying in shape and size. To elucidate mechanisms of variability in CYP3A4 catalysis, we examined the effects of genetic variants of POR, and explored the possibility that substrate-induced conformational changes in CYP3A4 differentially affect the ability of POR variants to support catalysis. Methods We expressed human CYP3A4 and four POR variants (Q153R, A287P, R457H, A503V) in bacteria, reconstituted them in vitro and measured the Michaelis constant and maximum velocity with testosterone, midazolam, quinidine and erythromycin as substrates. Results POR A287P and R457H had low activity with all substrates; Q153R had 76–94% of wild type (WT) activity with midazolam and erythromycin, but 129–150% activity with testosterone and quinidine. The A503V polymorphism reduced CYP3A4 activity to 61–77% of wild type with testosterone and midazolam, but had nearly wild type activity with quinidine and erythromycin. Conclusion POR variants affect CYP3A4 activities. The impact of a POR variant on catalysis by CYP3A4 is substrate-specific, probably due to substrate-induced conformational changes in CYP3A4.

These results suggest that genetic variations of MRP2 are an important predisposing factor for herbal-induced or drug-induced toxic liver injuries.