High Variability In Response Research Articles

Competing Pressures and Complex Choices

African Americans often live in crime-ridden communities, where the need to deter crime is high. They are also likely to be unjustly stopped by law enforcement authorities, arrested, incarcerated, and sentenced to death by the criminal justice system. This research argues that these competing pressures increase the complexity of choices African Americans must make when forming their preferences toward the death penalty. African Americans who are cross-pressured by insecurity (i.e., fear of victimization) and discrimination (i.e., fear of racial biases within the criminal justice system) exhibit more variation in the range of death penalty laws they find acceptable. Support for this claim is provided by cross-sectional survey data ( N = 514) of African Americans within the United States. A heteroscedastic item response theory model using these data shows that cross-pressured African Americans demonstrate high response variability (i.e., inconsistencies) in their acceptance of death penalty laws. Subsequently, the unique experience that African Americans have with the criminal justice system contributes to complex policy opinions that are rarely reflected in public policy or opinion polls.

High variability in the tissue culture response of root-tips of Allium ascalonicum individuals and optimization of the regeneration procedure

This study assessed the shoot regeneration capacity of root-tips isolated from single seed-derived individual plants, obtained from a wild, open-pollinated micropopulation of shallot (Allium ascalonicum). Considerable variation was observed in the regeneration capacities of individual lines, ranging from 0.93 to 100 %, and a mean bud number per root explant between 0.09 and 20.67. One line was found to be superior, and was chosen for protocol optimization, focusing on the 2,4-D/BA ratio, duration of the CI phase and light conditions. The application of the optimized protocol to other lines, selected for their variable regeneration capacities, enhanced the process of regeneration and shortened the time required to obtain healthy plantlets, even in inferior lines. However, highly responsive lines remained superior, indicating that differences at the individual level must not be overlooked. The conditions employed in this study may serve as a base to facilitate the application of molecular breeding methods in shallot.

Deriving site-specific soil clean-up values for metals and metalloids: rationale for including protection of soil microbial processes.

Although it is widely recognized that microorganisms are essential for sustaining soil fertility, structure, nutrient cycling, groundwater purification, and other soil functions, soil microbial toxicity data were excluded from the derivation of Ecological Soil Screening Levels (Eco-SSL) in the United States. Among the reasons for such exclusion were claims that microbial toxicity tests were too difficult to interpret because of the high variability of microbial responses, uncertainty regarding the relevance of the various endpoints, and functional redundancy. Since the release of the first draft of the Eco-SSL Guidance document by the US Environmental Protection Agency in 2003, soil microbial toxicity testing and its use in ecological risk assessments have substantially improved. A wide range of standardized and nonstandardized methods became available for testing chemical toxicity to microbial functions in soil. Regulatory frameworks in the European Union and Australia have successfully incorporated microbial toxicity data into the derivation of soil threshold concentrations for ecological risk assessments. This article provides the 3-part rationale for including soil microbial processes in the development of soil clean-up values (SCVs): 1) presenting a brief overview of relevant test methods for assessing microbial functions in soil, 2) examining data sets for Cu, Ni, Zn, and Mo that incorporated soil microbial toxicity data into regulatory frameworks, and 3) offering recommendations on how to integrate the best available science into the method development for deriving site-specific SCVs that account for bioavailability of metals and metalloids in soil. Although the primary focus of this article is on the development of the approach for deriving SCVs for metals and metalloids in the United States, the recommendations provided in this article may also be applicable in other jurisdictions that aim at developing ecological soil threshold values for protection of microbial processes in contaminated soils.

2D immunoblots show differential response of mouse IgG and IgM antibodies to antigens of mammary carcinoma 4 T1 cells

BackgroundImmunosuppression in breast cancer has been reported in women and in the highly metastatic mouse mammary tumor model 4 T1. The immunosuppressive environment complicates the use of the humoral response against the tumor as an immunodiagnostic tool. IgM has not been used in immunodiagnostic in part because its antitumor responses, both innate and adaptive, have not been studied in function of time in breast cancer.We show a new approach to analyzing the mouse humoral immune response, and compare the evolution with time of IgG and IgM responses against the antigens of 4 T1 cells.MethodsThe study is based on 2-dimensional immunoblotting detection of antigens from 4 T1 cells by the IgG and IgM antibodies in the serum of female mice injected with 4 T1 cells.ResultsThere was a high variability in the intra-and inter-mouse response. Variability in the IgM response was manifested as a pattern of spots that could become a multibinomial variable of 0 and 1, which could represent a signature of the immune response. Different numbers of spots was found in the IgG and IgM responses from week 1 to 5. On average, the IgM had more but the IgG response decrease with the time. The natural IgM at t = 0 responds stronger than w1; the adaptive response of both IgM and IgG were elicited where, with the former being stronger better than the latter. Antigens that are recognized by some female mice in the first week are also recognized by other female mice at time 0. Contamination of the natural IgM makes difficult use the adaptive IgM as a tool for immunodiagnostic.ConclusionsIgM and IgG response varied with the time and individuals. Spot variation in 2D pattern for the natural IgM could be expressed as a binomial signature, which opens up the way to correlate a particular pattern with resistance or susceptibility. This uncovers a battery of IgMs for each individual to confront cancer or infections. The possibility to differentiate between adaptive IgM antibodies from the natural IgM will allow investigation of the adaptive IgM for early immunodiagnosis.

Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was −0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (−0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (−0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (−0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy.

109. Multicenter evaluation of somatosensory evoked potentials (SEPs) normative data in infancy

Somatosensory evoked potentials (SEPs) represent a useful electrophysiological diagnostic tool in neuropediatry; normative data covering the full range of age, from neonate to adolescent, are rarely attainable from a single Laboratory. Purpose of the study was to collect normative data from several Laboratories to compare the reliability among laboratories; verify weather pooling of data can satisfy statistical requirement as if the data were collected in a single laboratory. Upper limbs and lower limbs SEP of 172 subjects from four Centers (Milan, Padua, Florence, Rome) were analysed. Age ranged from neonate to adolescents. Neonates and infants had a high variability of cortical responses; central conduction time (CCT) of the upper limbs was shorter than CCT of lower limbs; intra-spinal CCT of lower limbs was shorter than the cervical to cortical CCT; cortical upper limbs SEP grow faster than the lower limbs. The variability of cortical SEP in neonates and infancy probably reflects a variability of awake-sleep state but also the types of sensory fibres stimulated and the central sensory pathways organisation might play e role. Multicenter collection of SEP data is very useful to compare normative data, improve interpretation and deeper our knowledge on maturation of sensory systems.

Multimodal examination of emotion regulation difficulties as a function of co-occurring avoidant personality disorder among women with borderline personality disorder.

Despite a robust association between borderline personality disorder (BPD) and emotion dysregulation, evidence of within-BPD group differences in emotion regulation (ER) difficulties highlights the need to examine factors that increase the risk for ER difficulties within BPD. One factor that warrants consideration is co-occurring avoidant personality disorder (AVPD), the presence of which is associated with worse outcomes in and outside of BPD and theorized to interfere with adaptive ER. Thus, this study examined if co-occurring AVPD among women with BPD is associated with heightened ER difficulties (assessed across self-report, behavioral, and physiological domains). Participants included 39 women with BPD (13 with co-occurring AVPD) and 18 women without BPD. Although results revealed no significant differences in overall self-reported ER difficulties (or the specific dimensions involving emotional clarity and the control of behaviors when distressed) between BPD participants with and without AVPD (with both groups reporting greater ER difficulties than non-BPD participants), other ER difficulties were found to be heightened among BPD participants with AVPD. Specifically, BPD participants with (vs. without) AVPD reported greater difficulties accessing effective ER strategies, evidenced less willingness to experience distress on a laboratory stressor, and exhibited a greater decrease in high frequency heart rate variability in response to this stressor (indicative of poor ER capacity). Findings add to the literature on ER difficulties in BPD, suggesting that co-occurring AVPD within BPD may be associated with a lower capacity for regulating distress and greater difficulties accessing effective ER strategies, potentially leading to greater efforts to avoid emotional distress.

Maternal sensitivity and infant and mother adrenocortical function across challenges

Findings regarding associations between maternal sensitivity and infant and mother adrenocortical function have been inconsistent. Nor have studies addressed the issue of intra-individual, between-challenge cortisol variability in the context of maternal sensitivity. In this study, we combine several design features aimed at sensitizing analyses to these issues. Cortisol secretion of 297 infants and their mothers was assessed in response to different challenges at 16 and 17 months. Extensive, structured observations of maternal sensitivity were conducted at infant age 16 months. Data were analyzed with multilevel modeling using an actor-partner interdependence model. We found that maternal sensitivity was related to infant, but not maternal, cortisol levels and also to infant-mother cortisol attunement. Infants of more sensitive mothers, as compared to infants of less sensitive mothers, showed greater cortisol variability across challenges, with relatively steep cortisol decreases and increases, depending on challenge. Mother and infant cortisol levels were highly correlated and this attunement was higher among dyads with more sensitive mothers than among dyads with less sensitive mothers. The results show nuanced attunement in a low-risk sample, with the infants of higher sensitivity mothers showing greater intra-individual variability across challenges. High cortisol response variability across challenges may simultaneously permit adaptation to threat and protect the infant from overexposure to corticosteroids.

Dynamic response of tree growth to changing environmental pollution

Long-term investigations of Scots pine (Pinus sylvestris L.) growth were carried out in the vicinity of one of the biggest air pollution sources in Lithuania—mineral fertilizers plant “Achema.” It is detected that initial stages of the dynamic tree response to the external stress factors in the polluted environment with an increased quantity of nitrogen compounds have started with a stimulation stage, followed by a gradual transition to a depression of growth. The recovery of the damaged stands took place along with the reduced environmental pollution, and the overdraft of the “normal” annual increment was a characteristic feature of all the investigated stands. This phase is still continuing for the most damaged stands. A very high individual variability of the tree growth response to the environmental impact is a characteristic feature of the damaged Scots pine stands. The homeostatic mechanisms of the survived trees stipulated reaching approximately the same or even higher growth rate as prior to the depression period, and the tree growth rate before the depression period can serve as the most powerful predictor of tree growth recovery capacity under the reduced environmental pollution. Crown defoliation is the next most important predictor of individual tree recovery capacity. Lower stand density and lower competition cause higher recovery capacity of damaged trees. The conclusion is made that a reduction in the environmental pollution on the local and regional scale and especially a decrease in emissions and deposition of sulfur and nitrogen compounds caused the recovery of damaged forests. These trends should be taken into account while analyzing and modeling forest dynamics. Interaction of environmental pollution and climatic factors is very important for the response of tree growth to the environmental stressors.

Trends in Utilization of Transarterial Treatments for Hepatocellular Carcinoma: Results of a Survey by the Italian Society of Interventional Radiology

This study was designed to provide an overview of the practice of locoregional treatments for HCC by the Italian centers of Interventional Radiology (IR) with particular reference to transarterial modalities. A questionnaire of 11 questions on locoregional treatment of HCC was e-mailed to 134 Italian IR centers. The response rate was 64.9% (87/135 centers). Of 8,959 procedures in 2011, 67% were transarterial treatments, 31% percutaneous ablations, and 2% Y90-radioembolizations. Regarding (chemo)embolization, approximately 59% of procedures were performed in the intermediate stage, 28% in the early stage, and 12.8% in the advanced stage. TACE techniques varied greatly; approximately 52% of procedures were performed with drug-eluting particles and 32% with lipiodol, drug, and reabsorbable particles. In selected cases, 53 of 78 (68%) centers combine chemoembolization and ablation, whereas 28 centers (35.9%) combine Sorafenib and chemoembolization. In 2011, 13 of 78 (16.7%) responding centers performed Y90-radioembolization, with approximately 52% of procedures performed in the advanced stage and 46% in the intermediate stage. Approximately 62% of Y90-radioembolizations were performed using resin spheres and 38% using glass spheres. With almost 9,000 procedures performed each year, locoregional treatments of HCC, most of all transarterial (chemo)embolizations, represent a major part of daily clinical practice in many Italian IR centers. The high variability in responses regarding transarterial treatments for HCC patients highlights the need for solid scientific evidence allowing better definition of clinical indications and standardization of technical approaches.

Biomarkers for anti-angiogenic therapy in cancer.

Angiogenesis, the development of new vessels from existing vasculature, plays a central role in tumor growth, survival, and progression. On the molecular level it is controlled by a number of pro- and anti-angiogenic cytokines, among which the vascular endothelial growth factors (VEGFs), together with their related VEGF-receptors, have an exceptional position. Therefore, the blockade of VEGF signaling in order to inhibit angiogenesis was deemed an attractive approach for cancer therapy and drugs interfering with the VEGF-ligands, the VEGF receptors, and the intracellular VEGF-mediated signal transduction were developed. Although promising in pre-clinical trials, VEGF-inhibition proved to be problematic in the clinical context. One major drawback was the generally high variability in patient response to anti-angiogenic drugs and the rapid development of therapy resistance, so that, in total, only moderate effects on progression-free and overall survival were observed. Biomarkers predicting the response to VEGF-inhibition might attenuate this problem and help to further individualize drug and dosage determination. Although up to now no definitive biomarker has been identified for this purpose, several candidates are currently under investigation. This review aims to give an overview of the recent developments in this field, focusing on the most prevalent tumor species.

Affective Recommendation of Movies Based on Selected Connotative Features

The apparent difficulty in assessing emotions elicited by movies and the undeniable high variability in subjects' emotional responses to film content have been recently tackled by exploring film connotative properties: the set of shooting and editing conventions that help in transmitting meaning to the audience. Connotation provides an intermediate representation that exploits the objectivity of audiovisual descriptors to predict the subjective emotional reaction of single users. This is done without the need of registering users' physiological signals. It is not done by employing other people's highly variable emotional rates, but by relying on the intersubjectivity of connotative concepts and on the knowledge of user's reactions to similar stimuli. This paper extends previous work by extracting audiovisual and film grammar descriptors and, driven by users' rates on connotative properties, creates a shared framework where movie scenes are placed, compared, and recommended according to connotation. We evaluate the potential of the proposed system by asking users to assess the ability of connotation in suggesting film content able to target their affective requests.

Therapeutic drug monitoring detects high interpatient variability in response to mycophenolic acid treatment in patients with ANCA-associated vasculitis

Therapeutic drug monitoring detects high interpatient variability in response to mycophenolic acid treatment in patients with ANCA-associated vasculitis

A Continuous, Fluorescence-based Assay of µ-Opioid Receptor Activation in AtT-20 Cells

Opioids are widely prescribed analgesics, but their use is limited due to development of tolerance and addiction, as well as high variability in individual response. The development of improved opioid analgesics requires high-throughput functional assays to assess large numbers of potential opioid ligands. In this study, we assessed the ability of a proprietary “no-wash” fluorescent membrane potential dye to act as a reporter of µ–opioid receptor (MOR) activation and desensitization via activation of G-protein-coupled inwardly rectifying potassium channels. AtT-20 cells stably expressing mouse MOR were assayed in 96-well plates using the Molecular Devices FLIPR membrane potential dye. Dye emission intensity decreased upon membrane hyperpolarization. Fluorescence decreased in a concentration-dependent manner upon application of a range of opioid ligands to the cells, with high-efficacy agonists producing a decrease of 35% to 40% in total fluorescence. The maximum effect of morphine faded in the continued presence of agonist, reflecting receptor desensitization. The effects of opioids were prevented by prior treatment with pertussis toxin and blocked by naloxone. We have demonstrated this assay to be an effective method for assessing ligand signaling at MOR, which may potentially be scaled up as an additional high-throughput screening technique for characterizing novel opioid ligands.

Ozone Toxicity and Walking Response of Populations of &lt;I&gt;Sitophilus zeamais&lt;/I&gt; (Coleoptera: Curculionidae)

Ozone is a recognized alternative to the fumigants methyl bromide and phosphine for the control of stored product insects. However, as with fumigants in general, the potential sublethal effects of ozone on targeted insect species may compromise its efficacy and has yet to be investigated. Here, we determined ozone toxicity of 30 field-collected populations of the maize weevil, Sitophilus zeamais (Coleoptera: Curculionidae), and assessed the walking response of adult insects from these populations to sublethal ozone exposure. Time-mortality toxicity to ozone at 50 ppm concentration in a continuous 2 liter/min flow indicated uniform susceptibility among the populations studied without any indication of ozone resistance (toxicity ratios [at LT50] > two-fold). In contrast, there was significant variation in walking activity among the maize weevil populations, which was not correlated with ozone susceptibility. This was not surprising because of the relatively uniform susceptibility to ozone among the maize weevil populations. Respiration rate affected ozone toxicity but not walking activity, whereas body mass was negatively correlated with walking activity but was not correlated with ozone toxicity. Based on our data, lower respiration rates may potentially lead to reduced ozone uptake whereas larger body mass limits walking activity. Ozone seems a promising alternative fumigant with low short-term risk of resistance development because of the high susceptibility and low variability of response to this compound. Furthermore, ozone reduces walking activity of S. zeamais that implies it likely reduces the chances of insects escaping exposure at the early stages of fumigation.

Combination of prednisolone and low dosed dexamethasone exhibits greater in vitro antileukemic activity than equiactive dose of prednisolone and overcomes prednisolone drug resistance in acute childhood lymphoblastic leukemia

Glucocorticoids, particularly prednisone/ prednisolone and dexamethasone, play a prominent role in the treatment of pediatric patients with acute lymphoblastic leukemia due to their ability to induce apoptosis in susceptible cells. Current therapeutic protocols use prednisone for both the prophase and the induction phase of the therapy because the greater antileukemic activity of dexamethasone is compromised by its high frequency of serious adverse reactions. To compare, for the first time, the in vitro antileukemic activity of prednisolone alone to that of a combination of prednisolone and dexamethasone using dexamethasone at a very low and presumably safe dosage (1/50 w/w). Lymphoblasts were isolated from bone marrow and/or blood samples from children with newly diagnosed acute lymphoblastic leukemia. The cytotoxic activity of prednisolone, dexamethasone and the prednisolone/dexamethasone combination against isolated leukemia cells was analyzed using the MTT cytotoxicity assay. We observed differences in the in vitro antileukemic activity of prednisolone and dexamethasone in 21% of the tested patients. 3% of the children were prednisolone sensitive but dexamethasone resistant, while 18% were prednisolone resistant and dexamethasone sensitive. 32% were sensitive to both glucocorticoids and 18% were resistant to both. Cells from patients with good in vivo responses to prednisone monotherapy were more responsive to prednisolone in vitro than were cells from patients with poor prednisone responses (P<0.07). Importantly, we demonstrated that the use of even a minimal dose (1/50 w/w) of dexamethasone with prednisolone dramatically increases the in vitro anti-leukemic activity of prednisolone (P<0.0006). The high inter-individual variability of acute lymphoblastic leukemia responses to glucocorticoids suggest that either patients should be selected for prednisone or dexamethasone treatment on the basis of predictive biomarkers or that prednisone should be used directly in combination with a very low and safe dose of dexamethasone to potentiate its antileukemic activity. The latter option is likely to be cheaper and more efficient, and therefore warrants further clinical investigation to assess its efficacy and safety in treating childhood acute lymphoblastic leukemia.

Therapeutic Monitoring of Immunotherapies in Autoimmune Diseases

Immunosuppressive treatment still is an important element in the management of autoimmune mediated diseases. However, immunosuppressive therapy is often complicated by a narrow therapeutic index and high variability of treatment response. This review discusses the clinical management and monitoring strategies for the use of ciclosporin A, tacrolimus, azathioprine, mycophenolat mofetil, mitoxantrone and some monoclonal antibodies with focus on natalizumab.

Polymorphisms in genes OPRM1, β-arrestin 2, STAT6, and COMT and clinical outcome to opioid therapy.

9129 Background: Morphine sulfate is the most widely used opioid in oncologic pain. There is a high variability in response between individuals. The objectives are to correlate the variability in response (R) and tolerability with polymorphisms within OPRM1, β-arrestin 2, STAT6 and COMT gene sequences. Methods: DNA from 44 oncologic patients (pts) with an EVA score &gt; 6 was prospectively analyzed using allelic discrimination techniques and automatic sequencing. Pts (never treated with opioids) received morphine sulfate 10 mg per day. Pain was assessed by EVA score and toxicity was evaluated according to the most common opioid side effects. Symptomatology was reassessed after 72 hours. Chi-squared and Fisher’s tests where used to analyze data. Results: 17 pts (38.6%) responded with an EVA &lt; 3. 6 pts (13.6%) did not experience toxicity, 36 pts (81.8%) had mild side effects and 2 pts (4.5%) had severe side effects. There was no relation between R rate (RR) and tolerance. 76.5% of pts responding to treatment had a CC/CT β-arrestin 2 genotype and this was associated with a better RR (CC/CT R = 46.4% vs. TT R = 25% p = 0.16). The 2 pts having severe side effects belonged to CC/CT group. COMT genotypes AA/GA were associated with a higher RR (83.3%pts) and better tolerance (100% pts with no toxicities). OPRM1 genotype GG was associated with both treatment failure (0% responded) and worse tolerance (any toxicity = 100%; severe side effects = 33%). Only 2,4% pts in the AA/GA genotype experienced some toxicity (p = 0.041). Although STAT6 genotypes were not associated with RR, tolerance was better in those pts with an AA or GA genotype with 97.5% pts showing either mild or no side effects (p = 0.007). Conclusions: Common variants in β-arrestin 2, COMT, OPRM1 and STAT6 genes have shown to predict for opioid-associated response and side effects in oncologic patients. Further studies are needed to assess factors determining the variability in response and tolerance to opioid treatment.

Pharmacogenetics and Anesthetic Drugs

The incidence and potential for serious adverse drug reactions (SADRs) in anesthesia are high due to the narrow therapeutic indices of anesthetic and analgesic drugs and high interindividual variability in drug responses. Genetic factors contribute to a majority of these SADRs. Pharmacogenetics (PG), the study of genetic effects on drug action, is strongly related to the field of anesthesia; historically, succinylcholine apnea and malignant hyperthermia were among the first PG disorders reported. Recent years have strengthened this affiliation with an emerging wide base of knowledge of the effects of genetic variations on the pharmacodynamics and pharmacokinetics of anesthetic drugs. Here, we review the history of anesthetic PG, the important genes influencing enzymes involved in anesthetic drug metabolism, the influence of genotypic expression and the potential ramifications of recent discoveries on the practice of clinical anesthesia. Epigenetics and functional genomics are also discussed. The article also addresses various critical deficits in our current knowledge of PG related to anesthesia that account for the minimal clinical translation of the findings in this area in the present time. The review concludes that in addition to enhanced data generation facilitated by rapidly evolving genetic techniques, robust clinical study designs in a large sample and sound statistical analyses are essential prerequisites for the successful clinical implementation of research findings to individual perioperative care for every patient.

Abstract 1882: Gemcitabine pathway SNPs are associated with its PK parameters in patients with solid tumors

Abstract Gemcitabine (2′, 2′-difluoro 2′-deoxycytidine, dFdC) is a cytotoxic pyrimidine antimetabolite used as first-line chemotherapeutic agent for the treatment of a wide range of solid tumors and hematologic malignancies. It is as a pro-drug that undergoes cellular uptake through transporters like human equilibrative nucleoside transporter (hENT1/SLC29A1) and human concentrative nucleoside transporters (hCNT1/SLC28A1 and hCNT3/SLC28A3) followed by extensive intracellular phosphorylation by kinases like deoxycytidine kinase (DCK) and cytidine monophosphate kinase (CMPK) to its active diphosphorylated (dFdCDP) and triphosphorylated (dFdCTP) forms. Gemcitabine is primarily inactivated via deamination to its less potent metabolite 2′, 2′-difluorodeoxyuridine (dFdU) by cytidine deaminase (CDA). High inter-patient variability in response to gemcitabine treatment has been a major concern in gemcitabine chemotherapy. However, association of pharmacogenomics with gemcitabine pharmacokinetics (PK) has not been extensively studied so far. In the present study, therefore, we investigated association between single nucleotide polymorphisms (SNPs) within genes involved in gemcitabine transport/metabolic pathway and pharmacokinetic parameter estimates for gemcitabine and metabolites in patients diagnosed with solid tumors. Pharmacokinetic blood sampling (n=40) was as follows: pre-infusion, 5, 15, 30, 45 min, and 1, 1.25, 1.5, 2, 6, 24, 48 and 72 hours after the end of gemcitabine infusion. Gemcitabine and dFdU concentrations in plasma and intracellular dFdCTP levels in PBMCs were measured using HPLC-UV and LC MS/MS. A total of 86 SNPs in 14 genes viz. CDA, CMPK, CTPS, DCK, DCTD, NME1, NME2, NME3, NME4, NT5C2, NT5C3, SLC28A1, SLC28A3, and SLC29A1 were genotyped using Sequenom-based assays. Pharmacogenomic association was evaluated using Wilcoxon rank-sum test and Kruskal-Wallis one-way analysis of variance by ranks (p≤0.05). SNPs in 5′ nucleotidase genes- rs1163075, rs1926029, rs11598702 and rs1712517 in NT5C2 and rs3750117 in NT5C3 were associated with gemcitabine elimination clearance. SNPs in CDA- rs1048977 and rs4655226 were associated with dFdU clearance. SNPs in CTPS- rs4430318, rs61780437 and rs1044457 were strongly associated with higher dFdCTP formation clearance. Additionally, CDA, DCTD, SLC28A1, SLC28A3 and SLC29A1 SNPs were also associated with dFdCTP formation clearance. The results from our study indicate pharmacogenomic association between gemcitabine pharmacokinetic pathway SNPs and PK parameters. Presence of these SNPs could impact outcomes for patients receiving gemcitabine therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1882. doi:1538-7445.AM2012-1882