Publications by authors named "Jin-Sung Jang"

44 Publications

In vivo assessment of glutamine anaplerosis into the TCA cycle in human pre-malignant and malignant clonal plasma cells.

Cancer Metab 2020 Dec 11;8(1):29. Epub 2020 Dec 11.

Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.

Background: Overexpression of c-Myc is required for the progression of pre-malignant plasma cells in monoclonal gammopathy of undetermined significance (MGUS) to malignant plasma cells in multiple myeloma (MM). c-Myc also increases glutamine anaplerosis into the tricarboxylic acid (TCA) cycle within cancer cells. Whether increased glutamine anaplerosis is associated with the progression of pre-malignant to malignant plasma cells is unknown.

Methods: Human volunteers (N = 7) and patients with MGUS (N = 11) and MM (N = 12) were prospectively recruited to undergo an intravenous infusion of C-labeled glutamine followed by a bone marrow aspiration to obtain bone marrow cells and plasma.

Results: Despite notable heterogeneity, stable isotope-resolved metabolomics (SIRM) revealed that the mean C-labeled glutamine anaplerosis into the TCA cycle was higher in malignant compared to pre-malignant bone marrow plasma cells relative to the remainder of their paired bone marrow mononuclear cells. RNA sequencing demonstrated a higher relative mRNA expression of c-Myc and glutamine transporters such as ASCT2 and SN2 in malignant compared to pre-malignant bone marrow plasma cells. Finally, higher quantitative levels of TCA cycle intermediates in the bone marrow plasma differentiated MM from MGUS patients.

Conclusion: Measurement of the in vivo activity of glutamine anaplerosis into the TCA cycle provides novel insight into the metabolic changes associated with the transformation of pre-malignant plasma cells in MGUS to malignant plasma cells in MM.

Trial Registration: NCT03384108 and NCT03119883.
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http://dx.doi.org/10.1186/s40170-020-00235-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731537PMC
December 2020

Comparative evaluation for the globin gene depletion methods for mRNA sequencing using the whole blood-derived total RNAs.

BMC Genomics 2020 Dec 11;21(1):890. Epub 2020 Dec 11.

Medical Genome Facility, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.

Background: There are challenges in generating mRNA-Seq data from whole-blood derived RNA as globin gene and rRNA are frequent contaminants. Given the abundance of erythrocytes in whole blood, globin genes comprise some 80% or more of the total RNA. Therefore, depletion of globin gene RNA and rRNA are critical steps required to have adequate coverage of reads mapping to the reference transcripts and thus reduce the total cost of sequencing. In this study, we directly compared the performance of probe hybridization (GLOBINClear Kit and Globin-Zero Gold rRNA Removal Kit) and RNAse-H enzymatic depletion (NEBNext® Globin & rRNA Depletion Kit and Ribo-Zero Plus rRNA Depletion Kit) methods from 1 μg of whole blood-derived RNA on mRNA-Seq profiling. All RNA samples were treated with DNaseI for additional cleanup before the depletion step and were processed for poly-A selection for library generation.

Results: Probe hybridization revealed a better overall performance than the RNAse-H enzymatic depletion method, detecting a higher number of genes and transcripts without 3' region bias. After depletion, samples treated with probe hybridization showed globin genes at 0.5% (±0.6%) of the total mapped reads; the RNAse-H enzymatic depletion had 3.2% (±3.8%). Probe hybridization showed more junction reads and transcripts compared with RNAse-H enzymatic depletion and also had a higher correlation (R > 0.9) than RNAse-H enzymatic depletion (R > 0.85).

Conclusion: In this study, our results showed that 1 μg of high-quality RNA from whole blood could be routinely used for transcriptional profiling analysis studies with globin gene and rRNA depletion pre-processing. We also demonstrated that the probe hybridization depletion method is better suited to mRNA sequencing analysis with minimal effect on RNA quality during depletion procedures.
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http://dx.doi.org/10.1186/s12864-020-07304-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733259PMC
December 2020

TBK1 regulates regeneration of pancreatic β-cells.

Sci Rep 2020 11 9;10(1):19374. Epub 2020 Nov 9.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells.
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http://dx.doi.org/10.1038/s41598-020-76600-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653919PMC
November 2020

Maternal obesity is associated with phenotypic alterations in fetal immune cells by single-cell mass cytometry.

Am J Reprod Immunol 2021 03 4;85(3):e13358. Epub 2020 Nov 4.

Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.

Problem: Prenatal exposure to metabolic dysregulation arising from maternal obesity can have negative health consequences in post-natal life. To date, the specific effects of maternal obesity on fetal immunity at a cellular level have not been well characterized.

Method Of Study: Using cord blood mononuclear cells (CBMCs) and cord plasma (n = 9/group) isolated from infants born to women with a high body mass index (BMI>25kg/m ) compared to women with a normal BMI (18-25kg/m ), we evaluated differences in immune cell populations using single-cell mass cytometry (CyTOF). CBMCs were matched according to potentially confounding variables, such as maternal and gestational age, ethnicity, smoking status, and gravidity. Statistical results were adjusted for fetal sex. Data were analyzed by viSNE and FlowSOM softwares in Cytobank .

Results: In newborn CBMCs from women with high BMI, we observed changes in frequency and phenotype of immune cell populations, including significant increases in CD4 T cells and decreases in myeloid cell populations. IL-12p40 and MDC concentrations were significantly elevated in the high BMI group compared to control.

Conclusion: This study demonstrates an association between maternal obesity and fetal immunity. Our results warrant following long-term immunologic outcomes and associated clinical risks in children born to women with a high pre-pregnancy BMI.
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http://dx.doi.org/10.1111/aji.13358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109213PMC
March 2021

Single-cell mass cytometry on peripheral blood identifies immune cell subsets associated with primary biliary cholangitis.

Sci Rep 2020 07 28;10(1):12584. Epub 2020 Jul 28.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

The relationship between primary biliary cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood. Herein, we performed the first mass cytometry (CyTOF)-based, immunophenotyping analysis of the peripheral immune system in PBC at single-cell resolution. CyTOF was performed on peripheral blood mononuclear cells (PBMCs) from PBC patients (n = 33) and age-/sex-matched healthy controls (n = 33) to obtain immune cell abundance and marker expression profiles. Hierarchical clustering methods were applied to identify immune cell types and subsets significantly associated with PBC. Subsets of gamma-delta T cells (CD3TCRgd), CD8 T cells (CD3CD8CD161PD1), and memory B cells (CD3CD19CD20CD24CD27) were found to have lower abundance in PBC than in control. In contrast, higher abundance of subsets of monocytes and naïve B cells were observed in PBC compared to control. Furthermore, several naïve B cell (CD3CD19CD20CD24CD27) subsets were significantly higher in PBC patients with cirrhosis (indicative of late-stage disease) than in those without cirrhosis. Alternatively, subsets of memory B cells were lower in abundance in cirrhotic relative to non-cirrhotic PBC patients. Future immunophenotyping investigations could lead to better understanding of PBC pathogenesis and progression, and also to the discovery of novel biomarkers and treatment strategies.
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http://dx.doi.org/10.1038/s41598-020-69358-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387528PMC
July 2020

Decrease in the Risk of Posttransplant Hepatocellular Carcinoma Recurrence After the Conversion to Prestorage Leukoreduction for Transfused Red Blood Cells.

Transplantation 2021 03;105(3):577-585

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Prestorage leukoreduction has the advantage over poststorage leukoreduction in reducing leukocyte-derived molecules in red blood cells (RBC) unit, which induce immunomodulation. Our institution newly introduced prestorage leukoreduction, instead of conventional poststorage leukoreduction, for liver transplant recipients since March 2012. In this study, we aimed to evaluate the risk of posttransplant hepatocellular carcinoma (HCC) recurrence after the conversion of poststorage leukoreduction into prestorage leukoreduction for transfused allogeneic RBCs.

Methods: Among 220 patients who underwent living-donor liver transplantation for HCC, 83 of 113 who received only poststorage-leukoreduced RBCs were matched with 83 of 107 who received only prestorage-leukoreduced RBCs using 1:1 propensity score matching based on factors like tumor biology. The primary outcome was overall HCC recurrence. Survival analysis was performed with death as a competing risk event.

Results: In the matched cohort, recurrence probability at 1, 2, and 5 years posttransplant was 9.6%, 15.6%, and 18.1% in prestorage group and 15.6%, 21.6%, and 33.7% in poststorage group (hazard ratio [HR], 0.52; 0.28-0.97; P = 0.040). Multivariable analysis confirmed a significance of prestorage leukoreduction (HR, 0.29; 0.15-0.59; P < 0.001). Overall death risk was also lower with prestorage leukoreduction (HR, 0.51; 0.26-0.99; P = 0.049). In subgroup analysis for the unmatched cohort, recurrence risk was significantly lower in prestorage group within the patients who underwent surgery 2 years (HR, 0.24; 0.10-0.61; P = 0.002), 1 year (HR, 0.16; 0.03-0.92; P = 0.040), and 6 months (HR, 0.13; 0.02-0.85; P = 0.034), respectively, before and after the conversion to prestorage leukoreduction.

Conclusions: Our findings suggest a potential benefit of prestorage leukoreduction in reducing the risk of HCC recurrence in liver transplant recipients who received allogeneic RBCs during the perioperative period.
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http://dx.doi.org/10.1097/TP.0000000000003265DOI Listing
March 2021

Post-donation COVID-19 identification in blood donors.

Vox Sang 2020 11 21;115(8):601-602. Epub 2020 Apr 21.

Blood Services Headquarters, Korean Red Cross, Wonju, Korea.

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http://dx.doi.org/10.1111/vox.12925DOI Listing
November 2020

Donor protection: Iron supplementation for frequent blood donors in Korea.

Transfus Apher Sci 2020 Feb 9;59(1):102611. Epub 2019 Jul 9.

Department of Laboratory Medicine, Myongji-Hospital, 55, Hwasu-ro 14beon-gil, Deogyang-gu, Goyang-si, Gyeonggi-do, 10475, South Korea. Electronic address:

Objective: This study aimed to evaluate the effect of oral iron supplementation in frequent donors in Korea, based solely on donation history.

Study Design: The hemoglobin (Hb) level, ferritin level, soluble transferrin receptor (sTfR), total iron binding capacity (TIBC), and transferrin saturation of frequent donors at high risk for iron deficiency were compared to those of first donors. The frequent donors took iron supplements for 4 weeks and the same tests were repeated after 2 and 4 weeks to evaluate their effects.

Result: A total of 53 male and 57 female frequent donors were recruited. After 4-week iron supplementation, among the men, the prevalence of a: low Hb level (<13.0 g/dL) decreased from 25% to 2%; low ferritin level (<15.0 ng/mL) decreased from 58% to 4%; iron deficient erythropoiesis (IDE) (log(sTfR/ferritin) ≥ 2.07) decreased from 77% to 33%. Among the women, the percentage of a: low Hb level (<12.0 g/dL) decreased from 44% to 9%; low ferritin level decreased from 79% to 11%; IDE decreased from 95% to 47%. In total, 15 male (28.3%) and 29 female (56.9%) blood donors reported undesirable side effects related to iron supplementation. No serious adverse events were reported.

Conclusion: Ferritin level, a reliable indicator of iron status, increased and IDE decreased significantly after four-week iron supplementation in the female, but not in the male, donor group, compared to those of control donors. Four-week oral iron supplement was not enough to restore iron storage level in the male donor group.
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http://dx.doi.org/10.1016/j.transci.2019.07.005DOI Listing
February 2020

High frequency electrical stimulation promotes expression of extracellular matrix proteins from human astrocytes.

Mol Biol Rep 2019 Aug 2;46(4):4369-4375. Epub 2019 Jul 2.

Department of Neurologic Surgery, Mayo Clinic, Rochester, USA.

Therapeutic benefits of deep brain stimulation (DBS), a neurosurgical treatment for certain movement disorders and other neurologic conditions, are well documented, but DBS mechanisms remain largely unexplained. DBS is thought to modulate pathological neural activity. However, although astrocytes, the most numerous cell type in the brain, play a significant role in neurotransmission, chemical homeostasis and synaptic plasticity, their role in DBS has not been fully examined. To investigate astrocytic function in DBS, we applied DBS-like high frequency electrical stimulation for 24 h to human astrocytes in vitro and analyzed single cell transcriptome mRNA profile. We found that DBS-like high frequency stimulation negatively impacts astrocyte metabolism and promotes the release of extracellular matrix (matricellular) proteins, including IGFBP3, GREM1, IGFBP5, THBS1, and PAPPA. Our results suggest that astrocytes are involved in the long-term modulation of extra cellular matrix environments and that they may influence persistent cell-to-cell interaction and help maintain neuromodulation over time.
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http://dx.doi.org/10.1007/s11033-019-04890-9DOI Listing
August 2019

Bacterial Single Cell Whole Transcriptome Amplification in Microfluidic Platform Shows Putative Gene Expression Heterogeneity.

Anal Chem 2019 07 12;91(13):8036-8044. Epub 2019 Jun 12.

Single cell RNA sequencing is a technology that provides the capability of analyzing the transcriptome of a single cell from a population. So far, single cell RNA sequencing has been focused mostly on human cells due to the larger starting amount of RNA template for subsequent amplification. One of the major challenges of applying single cell RNA sequencing to microbial cells is to amplify the femtograms of the RNA template to obtain sufficient material for downstream sequencing with minimal contamination. To achieve this goal, efforts have been focused on multiround RNA amplification, but would introduce additional contamination and bias. In this work, we for the first time coupled a microfluidic platform with multiple displacement amplification technology to perform single cell whole transcriptome amplification and sequencing of Porphyromonas somerae, a microbe of interest in endometrial cancer, as a proof-of-concept demonstration of using single cell RNA sequencing tool to unveil gene expression heterogeneity in single microbial cells. Our results show that the bacterial single-cell gene expression regulation is distinct across different cells, supporting widespread heterogeneity.
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http://dx.doi.org/10.1021/acs.analchem.8b04773DOI Listing
July 2019

Molecular signatures of multiple myeloma progression through single cell RNA-Seq.

Blood Cancer J 2019 01 3;9(1). Epub 2019 Jan 3.

Genome Analysis Core, Medical Genome Facility, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.

We used single cell RNA-Seq to examine molecular heterogeneity in multiple myeloma (MM) in 597 CD138 positive cells from bone marrow aspirates of 15 patients at different stages of disease progression. 790 genes were selected by coefficient of variation (CV) method and organized cells into four groups (L1-L4) using unsupervised clustering. Plasma cells from each patient clustered into at least two groups based on gene expression signature. The L1 group contained cells from all MGUS patients having the lowest expression of genes involved in the oxidative phosphorylation, Myc targets, and mTORC1 signaling pathways (p < 1.2 × 10). In contrast, the expression level of these pathway genes increased progressively and were the highest in L4 group containing only cells from MM patients with t(4;14) translocations. A 44 genes signature of consistently overexpressed genes among the four groups was associated with poorer overall survival in MM patients (APEX trial, p < 0.0001; HR, 1.83; 95% CI, 1.33-2.52), particularly those treated with bortezomib (p < 0.0001; HR, 2.00; 95% CI, 1.39-2.89). Our study, using single cell RNA-Seq, identified the most significantly affected molecular pathways during MM progression and provided a novel signature predictive of patient prognosis and treatment stratification.
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http://dx.doi.org/10.1038/s41408-018-0160-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318319PMC
January 2019

Identification and Development of a Lung Adenocarcinoma PDX Model With STRN-ALK Fusion.

Clin Lung Cancer 2019 03 20;20(2):e142-e147. Epub 2018 Nov 20.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Biomarker Discovery Program, Mayo Clinic, Rochester, MN; The Genome Analysis Core, Center for Individualized Medicine, Mayo Clinic, Rochester, MN. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2018.11.002DOI Listing
March 2019

CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy.

JCI Insight 2018 04 19;3(8). Epub 2018 Apr 19.

Department of Urology.

Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy-responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.
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http://dx.doi.org/10.1172/jci.insight.97828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931117PMC
April 2018

Composite hemangioendothelioma with neuroendocrine marker expression: an aggressive variant.

Mod Pathol 2017 11 21;30(11):1589-1602. Epub 2017 Jul 21.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Aberrant expression of neuroendocrine markers is extremely rare in endothelial neoplasms, with only a single report describing three cases. Although originally classified as conventional angiosarcoma, further assessment of these tumors revealed a strikingly composite morphology composed of retiform and epithelioid elements reminiscent of composite hemangioendothelioma, a rare subtype of hemangioendothelioma. To further investigate these findings, available materials from 11 morphologically distinctive endothelial tumors showing neuroendocrine marker expression were retrieved from our archives. Immunohistochemistry for CD31, CD34, FLI-1, synaptophysin, chromogranin, D2-40, ERG, keratin (OSCAR), and CAMTA1 was performed. Total RNA from five cases were extracted and subjected to whole transcriptome sequencing. Clinical follow-up was obtained. These tumors were found to arise in five males and six females in patients from 9 to 55 years in age (median 47 years). They arose both in superficial (wrist, ankle, scalp, hip, and foot) and deep (periaortic tissues, C5 vertebra, pulmonary vein, and liver) locations. All contained elongated, retiform vascular channels lined by hyperchromatic 'hobnail' endothelial cells and a solid growth of uniform epithelioid cells reminiscent of epithelioid hemangioendothelioma. Hemangioma-like foci also lined by hobnail endothelial cells were frequently present. Mitotic activity was typically <1/10 HPF, and necrosis or areas of conventional angiosarcoma was absent. The results of immunohistochemistry were: CD31 (10/10), FLI-1 (10/10), ERG (9/9), CD34 (5/10), D2-40 (7/10), synaptophysin (11/11), chromogranin A (1/11), CD56 (5/11), keratin (0/11), and CAMTA1 (0/6). Sequencing analysis showed one case with PTBP1-MAML2 and one case with EPC1-PHC2 fusion transcripts; fusion transcripts were not identified in the remaining cases. Follow-up (8 cases) revealed local recurrence in one patient and metastatic spread in four individuals (bone, lung, liver, and brain). One person died of disease. Although the morphological features of these tumors are characteristic of composite hemangioendothelioma, this distinctive subset with neuroendocrine differentiation more often involves deep locations and displays more aggressive behavior than typically described in other cases of composite hemangioendothelioma.
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http://dx.doi.org/10.1038/modpathol.2017.83DOI Listing
November 2017

Perioperative Fresh Red Blood Cell Transfusion May Negatively Affect Recipient Survival After Liver Transplantation.

Ann Surg 2018 02;267(2):346-351

Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objective: The aim of this study is to evaluate the association between fresh red blood cell (RBC) transfusion and recipient survival after liver transplantation.

Background: Fresh RBC products contain many viable leukocytes. Allogeneic leukocytes are responsible for adverse transfusion reactions in the immunocompromised host.

Methods: Among 343 liver transplant recipients who underwent perioperative RBC transfusion, 91 of 226 who did not receive fresh RBCs were matched with 91 of 117 who received fresh RBCs with 1:1 matching ratio using the propensity score based on the amount of transfused blood products and others. Survival analysis was performed using the Cox model.

Results: All transfused 3230 RBCs were leukoreduced and irradiated. Before matching, recipients in fresh RBC group received 3 U (2-6 U) of fresh RBCs. After a median follow-up of 60 months, 60 of 343 recipients (17.5%) died. Survival probability at 1/2/5 years after transplantation was 94.7%/92.0%/85.8% for nonfresh RBC group and 82.9%/76.0%/72.0% for fresh RBC group [death hazard ratio (HR) = 2.37 (1.43-3.94), P = 0.001]. In multivariable analysis, fresh RBC transfusion was significantly associated with increased death risk [HR = 2.33 (1.35-4.01), P = 0.002]. After matching, recipients in fresh RBC group received 3 U (2-5 U) of fresh RBCs. After a median follow-up of 56 months, 35 of 182 recipients (19.2%) died. Survival probability at 1/2/5 years was 95.6%/93.2%/86.0% for nonfresh RBC group and 85.7%/78.0%/73.0% for fresh RBC group [HR = 2.23 (1.43-3.94), P = 0.028]. Multivariable analysis confirmed a significance of fresh RBC transfusion [HR = 3.20 (1.51-6.78), P = 0.002].

Conclusion: Our findings suggest a potential negative impact of fresh RBC transfusion on the survival of patients undergoing liver transplantation.
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http://dx.doi.org/10.1097/SLA.0000000000002062DOI Listing
February 2018

Custom Gene Capture and Next-Generation Sequencing to Resolve Discordant ALK Status by FISH and IHC in Lung Adenocarcinoma.

J Thorac Oncol 2016 11 22;11(11):1891-1900. Epub 2016 Jun 22.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Introduction: We performed a genomic study in lung adenocarcinoma cases with discordant anaplastic lymphoma receptor tyrosine kinase gene (ALK) status by fluorescent in situ hybridization (FISH) and immunohistochemical (IHC) analysis.

Methods: DNA from formalin-fixed paraffin-embedded tissues of 16 discordant (four FISH-positive/IHC-negative and 12 FISH-negative/IHC-positive) cases by Vysis ALK Break Apart FISH and ALK IHC testing (ALK1 clone) were subjected to whole gene capture and next-generation sequencing (NGS) of nine genes, including ALK, echinoderm microtubule associated protein like 4 gene (EML4), kinesin family member 5B gene (KIF5B), staphylococcal nuclease and tudor domain containing 1 gene (SND1), BRAF, ret proto-oncogene (RET), ezrin gene (EZR), ROS1, and telomerase reverse transcriptase (TERT). All discordant cases (except one FISH-negative/IHC-positive case without sufficient tissue) were analyzed by IHC with D5F3 antibody. In one case with fresh frozen tissue, whole transcriptome sequencing was also performed. Twenty-six concordant (16 FISH-positive/IHC-positive and 10 FISH-negative/IHC-negative) cases were included as controls.

Results: In four ALK FISH-positive/IHC-negative cases, no EML4-ALK fusion gene was observed by NGS, but in one case using fresh frozen tissue, we identified EML4-baculoviral AIP repeat containing 6 gene (BIRC6) and AP2 associated kinase 1 gene (AAK1)-ALK fusion genes. Whole transcriptome sequencing revealed a highly expressed EML4-BIRC6 fusion transcript and a minimally expressed AAK1 transcript. Among the 12 FISH-negative/IHC-positive cases, no evidence of ALK gene rearrangement was detected by NGS. Eleven of 12 FISH-negative/IHC-positive cases detected by ALK1 clone were concordant by repeat ALK IHC with D5F3 antibody (i.e., FISH-negative/IHC-negative by D5F3 clone). Among the 16 ALK FISH-positive/IHC-positive positive controls, whole gene capture identified ALK gene fusion in 15 cases, including in one case with Huntington interacting protein 1 gene (HIP1)-ALK. No ALK fusion gene was observed in any of the 10 FISH-negative/IHC-negative cases. Other fusion genes involving ROS1, EZR, BRAF, and SND1 were also found.

Conclusions: ALK FISH results appeared to be false-positive in three of four FISH-positive/IHC-negative cases, whereas no false-negative ALK FISH case was identified among 12 ALK FISH-negative/IHC-positive cases by ALK1 clone, which was in keeping with the concordant FISH-negative/IHC-negative status by D5F3 clone. Our targeted whole gene capture approach using formalin-fixed paraffin embedded samples was effective for detecting rearrangements involving ALK and other actionable oncogenes.
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http://dx.doi.org/10.1016/j.jtho.2016.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731243PMC
November 2016

Methanol-Tolerant Platinum-Palladium Catalyst Supported on Nitrogen-Doped Carbon Nanofiber for High Concentration Direct Methanol Fuel Cells.

Nanomaterials (Basel) 2016 Aug 15;6(8). Epub 2016 Aug 15.

Fuel Cell Research Center, Korea Institute of Energy Research (KIER), Daejeon 305-343, Korea.

Pt-Pd catalyst supported on nitrogen-doped carbon nanofiber (N-CNF) was prepared and evaluated as a cathode electrode of the direct methanol fuel cell (DMFC). The N-CNF, which was directly synthesized by the catalytic chemical vapor deposition from acetonitrile at 640 °C, was verified as having a change of electrochemical surface properties such as oxygen reduction reaction (ORR) activities and the electrochemical double layer compared with common carbon black (CB). To attain the competitive oxygen reduction reaction activity with methanol tolerance, the Pt and Pd metals were supported on the CB or the N-CNF. The physical and electrochemical characteristics of the N-CNF-supported Pt-Pd catalyst were examined and compared with catalyst supported on the CB. In addition, DMFC single cells using these catalysts as the cathode electrode were applied to obtain I-V polarization curves and constant current operating performances with high-concentration methanol as the fuel. Pt-Pd catalysts had obvious ORR activity even in the presence of methanol. The higher power density was obtained at all the methanol concentrations when it applied to the membrane electrode assembly (MEA) of the DMFC. When the N-CNF is used as the catalyst support material, a better performance with high-concentration methanol is expected.
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http://dx.doi.org/10.3390/nano6080148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224627PMC
August 2016

Common Oncogene Mutations and Novel SND1-BRAF Transcript Fusion in Lung Adenocarcinoma from Never Smokers.

Sci Rep 2015 May 18;5:9755. Epub 2015 May 18.

Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.

Lung adenocarcinomas from never smokers account for approximately 15 to 20% of all lung cancers and these tumors often carry genetic alterations that are responsive to targeted therapy. Here we examined mutation status in 10 oncogenes among 89 lung adenocarcinomas from never smokers. We also screened for oncogene fusion transcripts in 20 of the 89 tumors by RNA-Seq. In total, 62 tumors had mutations in at least one of the 10 oncogenes, including EGFR (49 cases, 55%), K-ras (5 cases, 6%), BRAF (4 cases, 5%), PIK3CA (3 cases, 3%), and ERBB2 (4 cases, 5%). In addition to ALK fusions identified by IHC/FISH in four cases, two previously known fusions involving EZR- ROS1 and KIF5B-RET were identified by RNA-Seq as well as a third novel fusion transcript that was formed between exons 1-9 of SND1 and exons 2 to 3' end of BRAF. This in-frame fusion was observed in 3/89 tested tumors and 2/64 additional never smoker lung adenocarcinoma samples. Ectopic expression of SND1-BRAF in H1299 cells increased phosphorylation levels of MEK/ERK, cell proliferation, and spheroid formation compared to parental mock-transfected control. Jointly, our results suggest a potential role of the novel BRAF fusion in lung cancer development and therapy.
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http://dx.doi.org/10.1038/srep09755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434945PMC
May 2015

Type 1 equilibrative nucleoside transporter regulates astrocyte-specific glial fibrillary acidic protein expression in the striatum.

Brain Behav 2014 19;4(6):903-14. Epub 2014 Sep 19.

Department of Psychiatry and Psychology, Mayo Clinic, College of Medicine Rochester, Minnesota, 55905 ; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine Rochester, Minnesota, 55905 ; Neurobiology of Disease Program, Mayo Clinic, College of Medicine Rochester, Minnesota, 55905.

Background: Adenosine signaling has been implicated in several neurological and psychiatric disorders. Previously, we found that astrocytic excitatory amino acid transporter 2 (EAAT2) and aquaporin 4 (AQP4) are downregulated in the striatum of mice lacking type 1 equilibrative nucleoside transporter (ENT1).

Methods: To further investigate the gene expression profile in the striatum, we preformed Illumina Mouse Whole Genome BeadChip microarray analysis of the caudate-putamen (CPu) and nucleus accumbens (NAc) in ENT1 null mice. Gene expression was validated by RT-PCR, Western blot, and immunofluorescence. Using transgenic mice expressing enhanced green fluorescence protein (EGFP) under the control of the glial fibrillary acidic protein (GFAP) promoter, we examined EGFP expression in an ENT1 null background.

Results: Glial fibrillary acidic protein was identified as a top candidate gene that was reduced in ENT1 null mice compared to wild-type littermates. Furthermore, EGFP expression was significantly reduced in GFAP-EGFP transgenic mice in an ENT1 null background in both the CPu and NAc. Finally, pharmacological inhibition or siRNA knockdown of ENT1 in cultured astrocytes also reduced GFAP mRNA levels.

Conclusions: Overall, our findings demonstrate that ENT1 regulates GFAP expression and possibly astrocyte function.
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http://dx.doi.org/10.1002/brb3.283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178301PMC
July 2015

MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma: molecular analysis of 25 ALK-positive cases.

J Thorac Oncol 2013 May;8(5):574-81

Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.

Introduction: Oncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non-small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization.

Methods: Using the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets.

Results: Five of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested.

Conclusions: In summary, additional mutations were found in 20% of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed.
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http://dx.doi.org/10.1097/JTO.0b013e318287c395DOI Listing
May 2013

Multi-platform analysis of microRNA expression measurements in RNA from fresh frozen and FFPE tissues.

PLoS One 2013 31;8(1):e52517. Epub 2013 Jan 31.

Medical Genome Facility Gene Expression Core, Mayo Clinic, Rochester, Minnesota, United States of America.

MicroRNAs play a role in regulating diverse biological processes and have considerable utility as molecular markers for diagnosis and monitoring of human disease. Several technologies are available commercially for measuring microRNA expression. However, cross-platform comparisons do not necessarily correlate well, making it difficult to determine which platform most closely represents the true microRNA expression level in a tissue. To address this issue, we have analyzed RNA derived from cell lines, as well as fresh frozen and formalin-fixed paraffin embedded tissues, using Affymetrix, Agilent, and Illumina microRNA arrays, NanoString counting, and Illumina Next Generation Sequencing. We compared the performance within- and between the different platforms, and then verified these results with those of quantitative PCR data. Our results demonstrate that the within-platform reproducibility for each method is consistently high and although the gene expression profiles from each platform show unique traits, comparison of genes that were commonly detectable showed that detection of microRNA transcripts was similar across multiple platforms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052517PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561362PMC
September 2013

SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling.

J Mol Med (Berl) 2013 Mar 12;91(3):381-93. Epub 2012 Sep 12.

Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.

The purpose of this study was to identify key genetic pathways involved in non-small cell lung cancer (NSCLC) and understand their role in tumor progression. We performed a genome wide scanning using paired tumors and corresponding 16 mucosal biopsies from four follow-up lung cancer patients on Affymetrix 250K-NSpI array platform. We found that a single gene SH3GL2 located on human chromosome 9p22 was most frequently deleted in all the tumors and corresponding mucosal biopsies. We further validated the alteration pattern of SH3GL2 in a substantial number of primary NSCLC tumors at DNA and protein level. We also overexpressed wild-type SH3GL2 in three NSCLC cell lines to understand its role in NSCLC progression. Validation in 116 primary NSCLC tumors confirmed frequent loss of heterozygosity of SH3GL2 in overall 51 % (49/97) of the informative cases. We found significantly low (p = 0.0015) SH3GL2 protein expression in 71 % (43/60) primary tumors. Forced overexpression of wild-type (wt) SH3GL2 in three NSCLC cell lines resulted in a marked reduction of active epidermal growth factor receptor (EGFR) expression and an increase in EGFR internalization and degradation. Significantly decreased in vitro (p = 0.0015-0.030) and in vivo (p = 0.016) cellular growth, invasion (p = 0.029-0.049), and colony formation (p = 0.023-0.039) were also evident in the wt-SH3GL2-transfected cells accompanied by markedly low expression of activated AKT(Ser(473)), STAT3 (Tyr(705)), and PI3K. Downregulation of SH3GL2 interactor USP9X and activated ß-catenin was also evident in the SH3GL2-transfected cells. Our results indicate that SH3GL2 is frequently deleted in NSCLC and regulates cellular growth and invasion by modulating EGFR function.
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http://dx.doi.org/10.1007/s00109-012-0955-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691869PMC
March 2013

Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers.

Clin Cancer Res 2012 Jul 9;18(13):3658-67. Epub 2012 May 9.

Division of Pulmonary and Critical Care Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.

Purpose: miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non-small cell lung cancer.

Experimental Design: We conducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells.

Results: Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08-3.35; P = 0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02-3.63; P = 0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 3' UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture.

Conclusions: miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-2857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616503PMC
July 2012

EGFR somatic mutations in lung tumors: radon exposure and passive smoking in former- and never-smoking U.S. women.

Cancer Epidemiol Biomarkers Prev 2012 Jun 20;21(6):988-92. Epub 2012 Apr 20.

Department of Radiobiology, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke.

Methods: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic.

Results: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors.

Conclusions: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-0166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372599PMC
June 2012

Characteristics of porous carbon nano-fibers synthesized by selective catalytic gasification.

J Nanosci Nanotechnol 2011 Jul;11(7):5775-80

Advanced Energy Technology, University of Science and Technology (UST), 113 Gwahangno, Yuseong-gu, Daejeon, 305-333, Republic of Korea.

Carbon nanofibers (CNFs) with uniquely oriented channels were prepared via selective catalytic gasification in air at 450 and 500 degrees C, using Pt or Ru nano particles as catalysts. Catalytic gasification was chosen because it can selectively generate channels in the vicinity of the catalyst particles at relatively low temperatures, where thermal oxidation does not intensively occur. The structures and surface properties of the CNFs were examined via X-ray diffraction, analysis of the nitrogen adsorption-desorption isotherms, and high-resolution transmission electron microscopy. The effects of the catalyst species and loading amount on the formation of pores (channels) were investigated. The gasification mechanism, especially the channeling direction, throught the selection of the gasification catalysts, is discussed based on the results. This process can be effectively utilized for preparation of porous carbons, which have a well-aligned graphitic structure, and also channel-type pores can be designed by selection of gasification catalysts and conditions. The present porous CNF can be applied for catalyst support in fuel cells, without further treatment (e.g., acid treatment for the removal of metallic components).
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http://dx.doi.org/10.1166/jnn.2011.4452DOI Listing
July 2011

In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome.

Am J Med Genet A 2012 Jan 21;158A(1):193-8. Epub 2011 Nov 21.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Cornelia de Lange Syndrome (CdLS) is a genetically heterogeneous disorder characterized by dysmorphic facial features, cleft palate, limb defects, growth retardation, and developmental delay. Approximately 60% of patients with CdLS have an identifiable mutation in the NIPBL gene at 5p13.2. Recently, an X-linked form of CdLS with a generally milder phenotype was attributed to mutation of the structural maintenance of chromosomes 1A gene (SMC1A) at Xp11.22. Relatively few CdLS patients with mutations in SMC1A are known; female carriers have minor facial dysmorphism and cognitive deficiency without major structural abnormalities. To date, all mutations identified in SMC1A are missense or small in-frame deletions that preserve the open reading frame of the gene and likely have a dominant-negative effect. We report on a female with monosomy X mosaicism and a phenotype suggestive of a severe form of CdLS who presented with growth and mental retardation, multiple congenital anomalies, and facial dysmorphism. Array CGH confirmed mosaic monosomy X and identified a novel deletion of SMC1A spanning multiple exons, suggesting a possible loss-of-function effect. Sequencing of both genomic and cDNA demonstrated an 8,152 bp deletion of genomic DNA from exon 13 to intron 16. Although a loss-of-function effect cannot be excluded, the resulting mRNA remains in-frame and is expressed in peripheral blood lymphocytes, suggesting a dominant-negative effect. We hypothesize that the size of this deletion compared to previously reported mutations may account for this patient's severe CdLS phenotype. The presence of mosaic monosomy X may also modify the phenotype.
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http://dx.doi.org/10.1002/ajmg.a.34360DOI Listing
January 2012

Quantitative miRNA expression analysis using fluidigm microfluidics dynamic arrays.

BMC Genomics 2011 Mar 9;12:144. Epub 2011 Mar 9.

Department of Pulmonary and Critical Care Medicine, Rochester, MN 55905, USA.

Background: MicroRNAs (miRNAs) represent a growing class of small non-coding RNAs that are important regulators of gene expression in both plants and animals. Studies have shown that miRNAs play a critical role in human cancer and they can influence the level of cell proliferation and apoptosis by modulating gene expression. Currently, methods for the detection and measurement of miRNA expression include small and moderate-throughput technologies, such as standard quantitative PCR and microarray based analysis. However, these methods have several limitations when used in large clinical studies where a high-throughput and highly quantitative technology needed for the efficient characterization of a large number of miRNA transcripts in clinical samples. Furthermore, archival formalin fixed, paraffin embedded (FFPE) samples are increasingly becoming the primary resource for gene expression studies because fresh frozen (FF) samples are often difficult to obtain and requires special storage conditions. In this study, we evaluated the miRNA expression levels in FFPE and FF samples as well as several lung cancer cell lines employing a high throughput qPCR-based microfluidic technology. The results were compared to standard qPCR and hybridization-based microarray platforms using the same samples.

Results: We demonstrated highly correlated Ct values between multiplex and singleplex RT reactions in standard qPCR assays for miRNA expression using total RNA from A549 (R = 0.98; p < 0.0001) and H1299 (R = 0.95; p < 0.0001) lung cancer cell lines. The Ct values generated by the microfluidic technology (Fluidigm 48.48 dynamic array systems) resulted in a left-shift toward lower Ct values compared to those observed by ABI 7900 HT (mean difference, 3.79), suggesting that the microfluidic technology exhibited a greater sensitivity. In addition, we show that as little as 10 ng total RNA can be used to reliably detect all 48 or 96 tested miRNAs using a 96-multiplexing RT reaction in both FFPE and FF samples. Finally, we compared miRNA expression measurements in both FFPE and FF samples by qPCR using the 96.96 dynamic array and Affymetrix microarrays. Fold change comparisons for comparable genes between the two platforms indicated that the overall correlation was R = 0.60. The maximum fold change detected by the Affymetrix microarray was 3.5 compared to 13 by the 96.96 dynamic array.

Conclusion: The qPCR-array based microfluidic dynamic array platform can be used in conjunction with multiplexed RT reactions for miRNA gene expression profiling. We showed that this approach is highly reproducible and the results correlate closely with the existing singleplex qPCR platform at a throughput that is 5 to 20 times higher and a sample and reagent usage that was approximately 50-100 times lower than conventional assays. We established optimal conditions for using the Fluidigm microfluidic technology for rapid, cost effective, and customizable arrays for miRNA expression profiling and validation.
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http://dx.doi.org/10.1186/1471-2164-12-144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062620PMC
March 2011

Polymorphisms in telomere maintenance genes and risk of lung cancer.

Cancer Epidemiol Biomarkers Prev 2009 Oct 22;18(10):2773-81. Epub 2009 Sep 22.

Department of Biochemistry, Kyungpook National University Hospital, Samduk 2a 50, Daegu, 700-412, Korea.

This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (P(trend) < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-09-0323DOI Listing
October 2009

Telomere length and the risk of lung cancer.

Cancer Sci 2008 Jul 29;99(7):1385-9. Epub 2008 Apr 29.

Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.

Telomeres play a key role in the maintenance of chromosome integrity and stability. There is growing evidence that short telomeres induce chromosome instability and thereby promote the development of cancer. We investigated the association of telomere length and the risk of lung cancer. Relative telomere length in peripheral blood lymphocytes was measured by quantitative polymerase chain reaction in 243 lung cancer patients and 243 healthy controls that were frequency-matched for age, sex and smoking status. Telomere length was significantly shorter in lung cancer patients than in controls (mean +/- standard deviation: 1.59 +/- 0.75 versus 2.16 +/- 1.10, P < 0.0001). When the subjects were categorized into quartiles based on telomere length, the risk of lung cancer was found to increase as telomere length shortened (P(trend) < 0.0001). In addition, when the median of telomere length was used as the cutoff between long and short telomeres, individuals with short telomeres were at a significantly higher risk of lung cancer than those with long telomeres (adjusted odds ratio = 3.15, 95% confidence interval = 2.12-4.67, P < 0.0001). When the cases were categorized by tumor histology, the effect of short telomere length on the risk of lung cancer was more pronounced in patients with small cell carcinoma than in those with squamous cell carcinoma and adenocarcinoma (P = 0.001, test for homogeneity). These findings suggest that shortening of the telomeres may be a risk factor for lung cancer, and therefore, the presence of shortened telomeres may be used as a marker for susceptibility to lung cancer.
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http://dx.doi.org/10.1111/j.1349-7006.2008.00831.xDOI Listing
July 2008
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