Cristiana Stefan - Academia.edu (original) (raw)

Papers by Cristiana Stefan

Supplementary Data from High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumo... more Supplementary Data from High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model

Purpose: Histone deacetylase inhibitors have emerged as potent anticancer compounds. Using a nude... more Purpose: Histone deacetylase inhibitors have emerged as potent anticancer compounds. Using a nude-mouse xenograft model, for the first time we evaluated the response of human gastrointestinal stromal tumors (GIST) carrying different oncogenic KIT mutations to panobinostat (LBH589), administered single or in combination with imatinib.Experimental Design: We grafted the human GIST882 cell line with KIT exon 13 mutation and two biopsies from patients radiologically progressing under imatinib showing KIT exon11 and KIT exon9 mutations, respectively. Our study included 4 groups: A (n = 9; control), B (n = 10; panobinostat 10 mg/kg daily, i.p.), C (n = 9; imatinib 150 mg/kg bidaily, p.o), and D (n = 8; combination panobinostat-imatinib, same dose/schedule as above). Treatment lasted 12 days. Tumor size was measured regularly using standard variables. Histopathological assessment was by H&E, and immunohistochemically with KIT, cleaved caspase-3, Ki-67, and histone acetylation staining.Resu...

Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) ... more Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3'-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Methods: Plasma (n=35) and urine (n=35) samples were sent to eight different laboratories, which employed similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Results: Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios 0.82-1.16) and were highly correlated (all Pearson r>0.96, P<0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P<0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than in urine, as was observed for NMR. Conclusions: Plasma is a very reliable biological source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Impact: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies.

BackgroundThe opioid overdose crisis has generated innovative harm reduction and drug market moni... more BackgroundThe opioid overdose crisis has generated innovative harm reduction and drug market monitoring strategies. In Toronto, Ontario, Canada, a multi-site drug checking service (DCS) pilot project was launched in October 2019. The project provides people who use drugs with information on the chemical composition of their substances, thereby increasing their capacity to make more informed decisions about their drug use and avoid overdose. DCS also provides real-time market monitoring to identify trends in the unregulated drug supply. MethodsSample data were obtained through analyses of drug and used paraphernalia samples submitted anonymously and free of charge to DCS in downtown Toronto from October 10, 2019 to April 9, 2020, representing the first six months of DCS implementation. Analyses were conducted in clinical laboratories using ultra high performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS), and liquid chromatography or gas chromatography-mass s...

Psychopharmacology, 2021

RATIONALE With alcohol and cannabis remaining the most commonly detected drugs in seriously and f... more RATIONALE With alcohol and cannabis remaining the most commonly detected drugs in seriously and fatally injured drivers, there is a need to understand their combined effects on driving. OBJECTIVES The present study examined the effects of combinations of smoked cannabis (12.5% THC) and alcohol (target BrAC 0.08%) on simulated driving performance, subjective drug effects, cardiovascular measures, and self-reported perception of driving ability. METHODS In this within-subjects, double-blind, double-dummy, placebo-controlled, randomized clinical trial, cannabis users (1-7 days/week) aged 19-29 years attended four drug administration sessions in which simulated driving, subjective effects, cardiovascular measures, and whole blood THC and metabolite concentrations were assessed following placebo alcohol and placebo cannabis (<0.1% THC), alcohol and placebo cannabis, placebo alcohol and active cannabis, and alcohol and active cannabis. RESULTS Standard deviation of lateral position in the combined condition was significantly different from the placebo condition (p < 0.001). Standard deviation of lateral position was also significantly different from alcohol and cannabis alone conditions in the single task overall drive (p = 0.029 and p = 0.032, respectively), from the alcohol alone condition in the dual task overall drive (p = 0.022) and the cannabis alone condition in the dual task straightaway drive (p = 0.002). Compared to the placebo condition, the combined and alcohol conditions significantly increased reaction time. Subjective effects in the combined condition were significantly greater than with either of the drugs alone at some time points, particularly later in the session. A driving ability questionnaire showed that participants seemed unaware of their level of impairment. CONCLUSION Combinations of alcohol and cannabis increased weaving and reaction time, and tended to produce greater subjective effects compared to placebo and the single drug conditions suggesting a potential additive effect. The fact that participants were unaware of this increased effect has important implications for driving safety.

Drug and Alcohol Dependence, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The Journal of Applied Laboratory Medicine, 2018

Clinical pharmacokinetics, Jan 12, 2018

Escitalopram is used for post-partum depression; however, there are limited pharmacokinetic data ... more Escitalopram is used for post-partum depression; however, there are limited pharmacokinetic data of escitalopram in milk and plasma of infants breastfed by women taking the drug. The objective of this study was to apply physiologically-based pharmacokinetic (PBPK) modelling to predict infant drug exposure (plasma area under the curve from time zero to infinity [AUC]) based on drug monitoring data of escitalopram in breast milk. Using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, we quantified escitalopram concentrations in milk samples of 18 breastfeeding women with escitalopram therapy at steady state, collected at three to five time points. The escitalopram concentrations in breast milk were used with infant feeding parameters from the literature to simulate infant daily dose. We used PK-Sim to develop an adult PBPK model for escitalopram and extrapolated it to a population of 1600 infants up to 12 months of age. An integration of the simulate...

Schizophrenia Research, 2017

Background: Cannabis use disorders (CUD) are common in schizophrenia (~25%) compared to the gener... more Background: Cannabis use disorders (CUD) are common in schizophrenia (~25%) compared to the general population (~3%). Tetrahydrocannabinol (THC), the principal psychoactive component in cannabis is fat-soluble, resulting in an extended period for cannabinoid elimination. While detection of cannabinoids in urine is indicative of prior cannabis exposure, time of last use is difficult to verify sustained abstinence for extended periods (e.g., 28-days) in chronic cannabis users. Therefore, we evaluated the utility of a sustained cannabis abstinence paradigm in patients with schizophrenia and non-psychiatric controls. Methods: Cannabis dependent patients (n = 19) and controls (n = 20) underwent 28-days of monitored cannabis abstinence facilitated with contingency management. Urine samples were taken twice weekly. Abstinence was evaluated using 1) Self-report; 2) Qualitative biochemical confirmation using MEDTOX; and 3) in a subset of participants (schizophrenia, n = 13; controls, n = 13) gas chromatography-mass spectrometry (GC-MS) was performed to obtain quantitative creatinine-normalized carboxy-THC (THC-COOH) metabolite levels b 20 ng/mL). Subjective assessments were used to assess behavioral correlates of cannabis abstinence and further supported time-dependent abstinence trajectories. Results: Abstinence rates of 42.1% (8/19) in patients and 55% (11/19) in controls (p = 0.53) were observed. Increased cannabis withdrawal symptoms in both patients and controls supported abstinence. Discussion: Our results suggest a feasible method for identification of short-term cannabis abstinence in individuals with schizophrenia at rates comparable to controls. Monitoring sustained abstinence may have implications for potential interventions for CUDs in schizophrenia.

Psychopharmacology, 2017

Background The dopamine D3 receptor (DRD 3) has been proposed as a target for drug development fo... more Background The dopamine D3 receptor (DRD 3) has been proposed as a target for drug development for the treatment of addictive disorders. Recently, the anxiolytic buspirone has been shown to have affinity for DRD 3 and DRD 4 , and interest in repurposing it for addictive disorders has grown. Methods Binding of [ 3 H]-(+)-PHNO in the rat cerebellum and striatum was used to measure occupancy by buspirone of DRD 3 or DRD 2 , respectively. Effects of buspirone in the rat gambling task (rGT) and the five-choice serial reaction time task (5-CSRTT) were examined. Results Buspirone occupied both the DRD 2 and DRD 3 at high doses and the DRD 3 , but not the DRD 2 , in the narrow dose range of 3 mg/kg. At 10 mg/kg, a disruption of performance on rGT was observed. All measures of performance on the rGT, except for perseverations, were affected at 3 mg/kg. On the 5-CSRTT, omissions were increased. Impairments in the rGT were not mimicked by the effects induced by satiation. Further, buspirone did not impair food-maintained responding under a progressive ratio schedule of reinforcement at any dose, suggesting that the effects of buspirone on the rGT cannot be explained by non-selective actions. Conclusions Although buspirone had effects on the rGT at the dose that selectively occupied the DRD 3 , the effects found do not parallel those found in previous studies of the effects of selective DRD 3 antagonists on the rGT. Thus, buspirone may impair performance on the rGT through actions at multiple receptor sites.

Clinical Toxicology, 2015

Solanum torvum berries, known as susumber or turkey berries, are prepared as part of traditional ... more Solanum torvum berries, known as susumber or turkey berries, are prepared as part of traditional Jamaican dishes usually served with cod and rice. Poisoning is rare. Although toxic compounds have never been definitively isolated, previous reports suggest toxicity results from inhibition of acetylcholinesterases. We present a case of susumber berry poisoning with detailed electromyographic studies and laboratory analysis. A 54-year-old woman presented to the Emergency Department (ED) complaining of vision, speech, and gait changes; emesis; and diffuse myalgias following consumption of susumber berries. The physical examination demonstrated an intact, lucid mental status, miosis, opsoclonus, severe dysarthria, dysmetria, mild extremity tenderness and weakness, and inability to ambulate. Her symptom constellation was interpreted as a stroke. Electromyography demonstrated a pattern of early full recruitment as well as myotonia during the period of acute toxicity. Additionally, solanaceous compounds, in particular solasonine and solanidine, were identified in leftover berries and the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s serum. Store-bought commercial berries and subsequent serum samples were free of such toxic compounds. EMG studies, together with a laboratory analysis of berries or serum can assist in the differential diagnosis of stroke, and provide both a prognostic screening and confirmation of suspected glycoside toxicity.

Biochemical Journal, 1997

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 26, 2015

The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to t... more The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3'-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Plasma (n=35) and urine (n=35) samples were sent to eight different laboratories, which employed similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios 0.82-1.16) and were highly correla...

British journal of cancer, Jan 5, 2008

Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-res... more Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant or -intolerant gastrointestinal stromal tumours (GIST). Several studies have identified unexpected rates of thyroid dysfunction with sunitinib treatment. We performed a prospective observational study with the aim of more accurately defining the incidence and severity of hypothyroidism in RCC or GIST patients receiving sunitinib. Thyroid function was assessed at baseline and on days 1 and 28 of each treatment cycle. Thyroid antibodies were assessed at baseline and during follow-up if abnormal thyroid function tests were recorded. Sixteen patients (27%) developed sub- or clinical hypothyroidism and required hormone replacement and 20 patients (34%) showed at least one elevated thyroid-stimulating hormone not requiring therapeutic intervention. Twenty patients (34%) did not develop any biochemical thyroid abnormality. Thus, sunitinib can induce (sub-) clinical hypothyroidism, warran...

Therapeutic Drug Monitoring, 2013

Purinergic Signalling, 2006

Journal of Cell Science, 2005

Autotaxin (NPP2) is an extracellular protein that is upregulated in various malignancies, includi... more Autotaxin (NPP2) is an extracellular protein that is upregulated in various malignancies, including breast and lung cancer. It potently stimulates cell proliferation, cell motility and angiogenesis, which is accounted for by its intrinsic lysophospholipase-D activity that generates the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate. Based on its structural similarities with the better characterized nucleotide pyrophosphatase/phosphodiesterase NPP1, it has always been assumed that NPP2 is also synthesized as a type-II integral membrane protein and that extracellular NPP2 is generated from this membrane precursor. We show here, however, using domain swapping and mutagenesis experiments as well as N-terminal protein sequencing, that NPP2 is actually synthesized as a pre-pro-enzyme and that the proteolytically processed protein is secreted. Following the removal of a 27-residue signal peptide by the signal peptidase, NPP2 is subsequently cleaved by proprotein converta...

Hepatology, 1998

Plasma cell differentiation antigen-1 (PC-1) is a 5Јectonucleotide pyrophosphatase that has been ... more Plasma cell differentiation antigen-1 (PC-1) is a 5Јectonucleotide pyrophosphatase that has been implicated in various processes including insulin-and nucleotidemediated signaling and cell growth. We show here that the expression of both PC-1 mRNA and protein in rat liver and in hepatoma cells is strictly growth-related. Thus, the level of PC-1 in FAO hepatoma cells increased with the cell density. PC-1 was not expressed in the neonatal rat liver, but gradually appeared in the first weeks of age, to reach adult levels around the weaning period. Furthermore, PC-1 protein and mRNA largely disappeared from the liver within 24 hours following a hepatectomy of 70%, but reappeared in the later phases (3-15 days) of the ensuing regeneration period. An equally rapid loss of PC-1 protein and mRNA could also be provoked in normal livers by the administration of the translational inhibitor, cycloheximide, but the transcriptional inhibitors, actinomycin D and ␣-amanitin, did not show these effects. Nuclear run-on assays revealed that the loss of PC-1 mRNA after hepatectomy or after the administration of cycloheximide was not caused by a decreased transcription of the PC-1 gene, suggesting that the level of PC-1 is controlled by an mRNA-stabilizing protein that is lost after hepatectomy and has a high turnover.

Future Oncology, 2007

Trabectedin (ET-743; Yondelis®) is a novel DNA-binding agent, originally derived from the marine ... more Trabectedin (ET-743; Yondelis®) is a novel DNA-binding agent, originally derived from the marine tunicate, Ecteinascidia turbinata, and now produced synthetically. The efficacy of trabectedin in patients with advanced soft-tissue sarcoma has been demonstrated in three Phase II studies involving 189 previously treated patients. A pooled analysis of data from these studies showed that trabectedin induced tumor control (objective responses plus disease stabilization) in approximately 50% of patients; median overall survival was 10.3 months and progression-free survival at 6 months was 19.8%, with 29.3% of patients alive at 2 years. Responses were achieved in patients who were resistant to both doxorubicin and ifosfamide. Trabectedin is generally well tolerated, with adverse events being noncumulative, reversible and manageable. Unlike other commonly used cytotoxic agents, trabectedin is not associated with cardiotoxicity or neurotoxicity and alopecia is rare. Trabectedin is an interest...