Therasa Kim

Naïve CD8 + T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment

Despite of the potential implications for cancer immunotherapy, conventional approaches using in vitro expanded CD8+ T cells have suboptimal outcomes, mostly due to loss of functionality from cellular exhaustion. We therefore investigated the phenotypic and functional differences among in vitro activated CD8+ T cells of three different sources, namely naïve (NTeff), memory (MTeff) and tumor-infiltrating lymphocytes (TILeff) from human and mice, to better understand mechanisms behind potent effector functions and potential for overcoming current limitations. In line with the greater proliferation activity and longer telomere lengths of NTeff populations, cells of naïve origin exhibited significantly less amounts of T cell exhaustion markers than those of MTeff and TILeff, and moreover, acquired distinct expression patterns of memory-promoting transcription factors, T-bet and Eomes, induced in a rapid and sustainable manner. NTeff cells appeared to have lower expression of Foxp1 and were refractory to apoptosis upon TGF-β conditioning, implying better survival potential and resistance to tumor-induced immune suppression. Of CD8+ T cell pools activated to tumor-specific CTLs, naïve cell generated effectors possessed the most potent cytotoxic activity, validating implications for use in rational design of adoptive immunotherapy.

Copy number variability analysis of pharmacogenes in patients with lymphoma, leukemia, hepatocellular, and lung carcinoma using The Cancer Genome Atlas data.

Objective Individual differences in drug efficacy and toxicity remain an important clinical concern. We investigated copy number variation (CNV) frequencies for pharmacogenes using The Cancer Genome Atlas dataset. Materials and methods One hundred and fifty-two pharmacogenes were selected from liver hepatocellular carcinoma, lung squamous cell carcinoma (LUSC), acute myeloid leukemia, and lymphoid neoplasm diffuse large B-cell lymphoma (DLBL). The germ line and somatic CNV frequencies were analyzed. Results We found CNVs with more than 1% frequency in drug-metabolizing enzymes including CYP2A6, CYP2D6, GSTP1, CYP2E1, GSTM1, GSTT1, and SULT1A1, drug transporters such as SLC19A1 and SLC28A1, and targets such as FHIT in normal tissue or blood. GSTM1 had the highest frequency for gene gain (45.45, 39.18, 31.01, and 34.77%, respectively) and for gene loss (18.18, 29.38, 20.89, and 26.68%, respectively) in DLBL, acute myeloid leukemia, liver hepatocellular carcinoma, and LUSC. P2RY12 and P2RY1 had the highest frequency for gene gain in LUSC (26.95 and 26.68%, respectively) whereas ABCB1 and ABL2 had the highest frequency for gene gain in DLBL (27.27%) in cancer tissue or blood. Conclusion Germ line and somatic CNVs of pharmacogenes may play a role in determining individual variations in drug responses. Inclusion of CNVs in pharmacogenetic variations holds promise as biomarkers that can increase the benefits and reduce the risks of drug therapy on an individual level.

Population pharmacokinetics and pharmacodynamics of busulfan with GSTA1 polymorphisms in patients undergoing allogeneic hematopoietic stem cell transplantation.

AIM A population pharmacokinetic (PPK) analysis was conducted to describe the influence of GSTA1 polymorphisms on intravenous busulfan in adults undergoing allogeneic hematopoietic stem cell transplantation. PATIENTS & METHODS A PPK model was developed from 36 patients by a one-compartment model with first-order elimination. RESULTS The typical value of clearance and volume of distribution were 11.0 l/h and 42.4 l, respectively. Clearance decreased by 15% and area under the concentration-time curves (AUCs) increased with GSTA1 variants compared with wild-type (both p < 0.05). Subtherapeutic AUCs were seen only in wild-type patients. CONCLUSION To our knowledge, this is the first PPK study to suggest that GSTA1 polymorphisms in adults are associated with busulfan PK.

Pharmacogenomic biomarker information in FDA-approved paediatric drug labels.

Gene maturation differs between paediatric and adult populations, and the extrapolation of adult pharmacogenomic information to paediatrics is not always appropriate. We sought to determine the extent of paediatric pharmacogenomic trial translation into US FDA‐approved labels and to evaluate needs for biomarker studies. Using FDAs Table of Genomic Biomarkers and Drugs@FDA website, 38 pharmacogenomic biomarkers in 56 drug labels were identified with possible application in paediatrics. Of these 56 drugs, biomarker comparison against ‘Very Important Pharmacogenes (VIPs)’ defined in PharmGKBs database revealed a total of eight VIPs labelled among 41 drugs. One hundred and thirty‐nine product reviews posted on the FDA website under the Best Pharmaceuticals for Children Act and Paediatric Research Equity Act between October 2007 and July 2014 were examined. Review screening identified 43 drugs with ‘pharmacogenomic’ content, of which only three were true genotyping study reviews for proton pump inhibitors, all evaluating CYP2C19 polymorphisms. Pantoprazole was the sole drug labelled with pharmacogenomic information obtained specifically from paediatric trials. Clinicaltrials.gov was searched to further evaluate the current availability of pharmacogenomic studies in the paediatric population. Of the 33,132 trials registered on Clinicaltrials.gov, 137 were labelled as paediatric pharmacogenetic and pharmacogenomic studies. Pharmacogenomic studies directly conducted in paediatric patients are lacking, and thus, pharmacogenomic biomarker information based on adult studies is commonly presented in FDA‐approved labels for use in paediatric patients. Considering differences in gene expression and physiological maturation between paediatric and adult populations, studies investigating pharmacogenomic effects specifically in paediatric patients should be conducted whenever significant biomarkers are available.

Genetic polymorphisms of CASR and cancer risk: evidence from meta-analysis and HuGE review.

Background CASR gene appears to be involved in cancer biology and physiology. However, a number of studies investigating CASR polymorphisms and cancer risks have presented inconclusive results. Thus, a systematic review and a meta-analysis of the effect of CASR polymorphisms on several cancer risks were performed to suggest a statistical evidence for the association of CASR polymorphisms with cancer risks. Methods MEDLINE, EMBASE, Web of Science, Scopus, and the HuGE databases were searched. Nineteen articles of case–control and cohort studies were included for the final analysis. Results The colorectal cancer risk was reduced in proximal (odds ratio [OR] =0.679, P=0.001) and distal (OR =0.753, P=0.026) colon sites with GG genotype of CASR rs1042636 and increased in distal colon site (OR =1.418, P=0.039) with GG genotype of rs1801726 by additive genetic model. The rs17251221 demonstrated noticeable associations that carrying a homozygote variant increases breast and prostate cancer risk considerably. Conclusion The significant association of CASR polymorphisms with several cancer risks was observed in this review. In particular, the act of CASR polymorphisms as a tumor suppressor or an oncogene differs by cancer site and can be the research target for tumorigenesis.

Clinical impact of induction treatment modalities and optimal timing of radiotherapy for the treatment of limited-stage NK/T cell lymphoma

This study retrospectively investigated the optimal timing of radiotherapy (RT) in patients with limited-stage extranodal NK/T-cell lymphoma (ENTKL). Among 158 patients with newly diagnosed stage I/II ENKTL, 61 patients were treated with sequential chemotherapy followed by radiotherapy (SCRT), 55 with concurrent chemoradiotherapy followed by non-anthracycline-based chemotherapy (CCRT/CT), and 42 with chemotherapy (CT) only. The 5-year overall survival (OS) rate did not differ between SCRT (77.7±5.5%) and CCRT/CT (68.9±6.8%; p=0.234). In the SCRT group, 18 patients (29.5%) relapsed within the RT field and 6 (9.8%) at systemic sites, while in the CCRT/CT group, 9 patients (16.4%) relapsed at the primary site and 14 (25.5%) at systemic sites. The 5-year cumulative incidence of relapse (CIR) at primary sites was 26.3% and 19.2% after SCRT and CCRT/CT (p=0.308), while the 5-year CIR of systemic sites was 8.7% and 26.5% after SCRT and CCRT/CT, respectively (p=0.010). In the multivariate analysis, NK/T-cell Prognostic Index score and CR achievement were the most important prognostic factors for survival. Although up-front RT had limitations in systemic disease control and was associated with an increased risk of systemic relapse during RT compared to SCRT, timing of RT did not significantly affect survival outcomes.

Identification of Hanwoo Using 3'-tailed Primer Associated with Single Nucleotide Polymorphism (SNP) in Melanocortin 1 Receptor (MC1R) gene

To improve the methods used for the identification of Hanwoo, we performed a PCR using 3 -tailed primer associated with single nucleotide polymorphism(SNP) in Melanocortin 1 receptor(MCIR) gene. MCIR plays an important role in melanin synthesis and the SNP within MCIR was used as a target for PCRRFLP studies previously. A forward 3 -tailed primer, which matches with the template DNA of Hanwoo but not with others(blackhaired; Holstein and Black angus) at the site of 594th base sequence, and one reverse primer were designed for this study. When use this primer set, a size of 343bp was amplified by PCR only in Hanwoo, not in Holstein and Black angus. This result suggests that the PCR using our 3 -tailed primer would be very accurate, easy, reproducible and economic method to discriminate between Hanwoo meat and other black-haired ones.

Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

OBJECTIVES To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. MATERIALS Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). METHOD The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. RESULTS Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. CONCLUSION Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners.

Association between interleukin-10 promoter gene polymorphisms and acute graft-versus-host disease after hematopoietic stem cell transplantation: A systematic review and meta-analysis

Abstract Objectives Interleukin-10 (IL-10) is an important immunomodulatory cytokine. The association between IL-10 promoter gene polymorphisms and acute graft-versus-host disease (aGVHD) risk is established; however, results of these studies remain inconclusive. We performed a meta-analysis to clarify the effects of IL-10 promoter gene polymorphisms on aGVHD risk. Methods The authors searched MEDLINE, EMBASE, and Cochrane Library databases. Two independent authors extracted data, and the effects were estimated from an odds ratio (OR) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses identified sources of heterogeneity. Results Finally, a total of 11 studies encompassing 3588 recipients and 3221 donors were included to study IL-10 -1082 G > A, -819 C > T, and -592 C > A polymorphisms. IL-10 -819 CC genotype was associated with an increased aGVHD risk (grade I–IV: OR, 2.722 (95% CI, 1.360–5.450); grade II–IV: OR, 2.265 (95% CI, 1.015–5.053)). Furthermore, patients who received grafts from donors with an IL-10 -819 CC genotype experienced more frequent grade I–IV aGVHD (OR, 2.306 (95% CI, 1.168–4.551)). Recipients with IL-10 -592 CC genotypes were at increased risk for grade II–IV aGVHD (OR, 1.999 (95% CI, 1.230–3.250)). Together, this meta-analysis found that IL-10 -819 CC and -592 CC polymorphisms increased aGVHD risk. Discussion and Conclusion This meta-analysis found the evidence that the IL-10 -819 CC and -592 CC genotypes in both recipients and donors increased the risk of aGVHD in allogeneic hematopoietic stem cell transplantation (HSCT) patients. These results contribute towards improving patient outcome through insight and rationale for individualized treatment strategies considering genetic determinants.

FRI0235 Comparison on Radiographic Progression for 5 Years Between Juvenile Onset Ankylosing Spondylitis and Adult Onset Ankylosing Spondylitis: Observation Study of Korean Spondyloarthropathy Registry (OSKAR) Data

Background The most unique feature in ankylosing spondylitis (AS) is subchondral eburnation and syndesmophytes, possibly leading to ankylosis and spinal fusion. So far a few comparisons of spinal bone formation between adult onset AS (AoAS) and Juvenile onset AS (JoAS) have been done. However, prospective studies of this comparison have not been accomplished. Objectives The aim of this study was to evaluate difference of radiographic progression over 5 years between JoAS and AoAS. Methods A total of 533 patients (115 patients with JoAS, 418 patients with AoAS) from the Observation Study of Korean spondyloArthropathy Registry (OSKAR) cohort were enrolled. We used a two-step approach to compare the radiographic progression between the JoAS and the AoAS. First, all OSKAR data were analyzed in relation to the onset of disease on cross-sectional survey. Second, we analyzed the radiographic spinal progression between groups over 5 years. The modified Stoke AS Spinal Score (mSASSS) were examined by two experienced radiologists to validate the results. The collection of the clinical parameters was conducted to investigate the associations between clinical factors and the radiographic progression. Univariable and multivariable regression analyses were done after adjusting for potential confounding factors, such as age, gender, disease duration, history of peripheral arthritis, baseline CRP level, baseline mSASSS, and NSAID intakes). Results The agreement between the two readers regarding mSASSS was very good: ICC coefficient 0.75 (95% CI 0.61-0.82) and 0.71 (95% CI 0.58-0.82) at each time. On cross-sectional survey, in spite of adjusting for multiple comparisons by Bonferroni correction, the patients with JoAS had fewer mSASSS unit than those with AoAS (14.12±1.30 vs 18.58±0.85, p=0.005). In analysis over 5 years, the mean progression of mSASSS in patients with JoAS was 0.21±1.29 units, while that of mSASSS in patients with AoAS was 4.00±0.59 units (p=0.012). Conclusions The patients with JoAS had slower radiographic spinal damage progression over 5 years than those with AoAS. Disclosure of Interest None declared