38 research outputs found
Synthesis and Quantitative StructureâActivity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53.
The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed
Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia
Smartphone Delivery of Mobile HIV Risk Reduction Education
We sought to develop and deploy a video-based smartphone-delivered mobile HIV Risk Reduction (mHIVRR) intervention to individuals in an addiction treatment clinic. We developed 3 video modules that consisted of a 10-minute HIVRR video, 11 acceptability questions, and 3 knowledge questions and deployed them as a secondary study within a larger study of ecological momentary and geographical momentary assessments. All 24 individuals who remained in the main study long enough completed the mHIVRR secondary study. All 3 videos met our a priori criteria for acceptability âas isâ in the population: they achieved median scores of â¤2.5 on a 5-point Likert scale; â¤20% of the individuals gave them the most negative rating on the scale; a majority of the individuals stated that they would not prefer other formats over video-based smartphone-delivered one (all P<0.05). Additionally, all of our video modules met our a priori criteria for feasibility: â¤20% of data were missing due to participant noncompliance and â¤20% were missing due to technical failure. We concluded that video-based mHIVRR education delivered via smartphone is acceptable, feasible and may increase HIV/STD risk reduction knowledge. Future studies, with pre-intervention assessments of knowledge and random assignment, are needed to confirm these findings
Gene variants and educational attainment in cannabis use: mediating role of DNA methylation
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Using iPSCâderived human DA neurons from opioidâdependent subjects to study dopamine dynamics
Abstract Introduction: The dopaminergic (DA) system plays important roles in addiction. However, human DA neurons from drugâdependent subjects were not available for study until recent development in inducible pluripotent stem cells (iPSCs) technology. Methods: In this study, we produced DA neurons differentiated using iPSCs derived from opioidâdependent and control subjects carrying different 3ⲠVNTR (variable number tandem repeat) polymorphism in the human dopamine transporter (DAT or SLC6A3). In addition, the effects of valproic acid (VPA) exposures on iPSCâderived human DA neurons are also examined. Results: We present the first evidence suggesting that the 3ⲠVNTR polymorphism in the hDAT gene affects DAT expression level in iPSCâderived human DA neurons. In human DA neurons, which provide an appropriate cellular milieu, VPA treatment alters the expression of several genes important for dopaminergic neuron function including DAT, Nurr1, and TH; this might partly explain its action in regulating addictive behaviors. VPA treatment also significantly increased DA D2 receptor (Drd2) expression, especially in the opioidâdependent iPSC cell lines. Conclusions: Our data suggest that human iPSCâderived DA neurons may be useful in in vitro experimental model to examine the effects of genetic variation in gene regulation, to examine the underlying mechanisms in neurological disorders including drug addiction, and to serve as a platform for therapeutic development