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26.  Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines 
PLoS Pathogens  2016;12(12):e1006064.
CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin-based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses. Vaccination by the subcutaneous or the intranasal route stimulated systemic and mucosal CTL memory respectively. However, only CTL memory induced by intranasal vaccination was protective against influenza viral challenge, and correlated with an enhancement of memory CTLs in the airways and CD103+ CD69+ CXCR3+ resident memory-like CTLs in the lungs. Mechanistically, Myd88-deficient mice mounted primary CTL responses to Adjuplex vaccines that were similar in magnitude to wild-type mice, but exhibited altered differentiation of effector cell subsets. Immune potentiating effects of Adjuplex entailed alterations in the frequency of antigen-presenting-cell subsets in vaccine draining lymph nodes, and in the lungs and airways following intranasal vaccination. Further, Adjuplex enhanced the ability of dendritic cells to promote antigen-induced proliferation of naïve CD8 T cells by modulating antigen uptake, its intracellular localization, and rate of processing. Taken together, we have identified an adjuvant that elicits both systemic and mucosal CTL memory to non-replicating antigens, and engenders protective CTL-based heterosubtypic immunity to influenza A virus in the respiratory tract. Further, findings presented in this manuscript have provided key insights into the mechanisms and factors that govern the induction and programming of systemic and protective memory CTLs in the respiratory tract.
Author Summary
Current respiratory-virus vaccines typically employ non-replicating antigens and rely solely on the generation of humoral responses for protection. Viruses such as influenza can mutate and escape these responses, thereby limiting immunity and necessitating revaccination. Cell-mediated immunity (CMI) could provide broader protection by targeting viral components that infrequently mutate, however non-replicating vaccines capable of inducing CMI are not available. Impediments to vaccine development include an incomplete understanding of the nature of protective respiratory CMI and a lack of vaccine adjuvants capable of eliciting CMI to non-replicating antigens. Using a mouse model, we characterized the protective immunity afforded by CMI responses to non-replicating vaccines formulated with the adjuvant Adjuplex. We found that vaccination via either the subcutaneous or intranasal route was capable of inducing potent CMI responses. However, only intranasal vaccination protected against challenge with heterosubtypic influenza viruses. This protection correlated with enhancement of T cells with a resident-memory phenotype in the lungs. Additionally, mechanistic studies showed that Adjuplex affects antigen-presenting cells via activation and alteration of antigen uptake, processing, and presentation. The current studies: (1) identified an adjuvant that elicits protective CMI to respiratory viral pathogens; (2) suggested that stimulation of protective CMI in the respiratory tract requires intranasal vaccine delivery.
PMCID: PMC5173246  PMID: 27997610
27.  Molecular and Serological Survey of Selected Viruses in Free-Ranging Wild Ruminants in Iran 
PLoS ONE  2016;11(12):e0168756.
A molecular and serological survey of selected viruses in free-ranging wild ruminants was conducted in 13 different districts in Iran. Samples were collected from 64 small wild ruminants belonging to four different species including 25 Mouflon (Ovis orientalis), 22 wild goat (Capra aegagrus), nine Indian gazelle (Gazella bennettii) and eight Goitered gazelle (Gazella subgutturosa) during the national survey for wildlife diseases in Iran. Serum samples were evaluated using serologic antibody tests for Peste de petits ruminants virus (PPRV), Pestiviruses [Border Disease virus (BVD) and Bovine Viral Diarrhoea virus (BVDV)], Bluetongue virus (BTV), Bovine herpesvirus type 1 (BHV-1), and Parainfluenza type 3 (PI3). Sera were also ELISA tested for Pestivirus antigen. Tissue samples including spleen, liver, lung, tonsils, mesenteric and mediastinal lymph nodes and white blood cells (WBCs) were tested using polymerase chain reaction (PCR) for PPRV, Foot and Mouth Disease virus (FMDV), Pestivirus, BTV, Ovine herpesvirus type 2 (OvHV-2) and BHV-1. Serologic tests were positive for antibodies against PPRV (17%), Pestiviruses (2%) and BTV (2%). No antibodies were detected for BHV-1 or PI3, and no Pestivirus antigen was detected. PCR results were positive for PPRV (7.8%), FMDV (11%), BTV (3%), OvHV-2 (31%) and BHV-1 (1.5%). None of the samples were positive for Pestiviruses.
PMCID: PMC5173247  PMID: 27997620
28.  Effectiveness of Teriparatide on Fracture Healing: A Systematic Review and Meta-Analysis 
PLoS ONE  2016;11(12):e0168691.
Nowadays, the efficacy of teriparatide in treating osteoporosis was widely accepted, but the discussion about using teriparatide to enhance fracture healing hasn’t come to an agreement. This meta-analysis was conducted to evaluate the effectiveness of teriparatide for fracture healing.
We searched PubMed, the Cochrane Library, and Embase in August 2016 for randomized controlled trials (RCTs) which concerned the treatment of teriparatide for fracture healing.
Finally, a total of 380 patients were randomly assigned in the 5 trials included in this meta-analysis. There was a significant effectiveness with regards to function improvement in patients following fracture, however, there was no significant effectiveness with regards to time of radiographic fracture healing, fracture healing rate and reduction in pain.
This analysis showed that administration of teriparatide following fracture lacked the effectiveness for fracture healing. Moreover, teriparatide administration had no apparent adverse effects. These results should be interpreted with caution because of some clear limitations. If we want to confirm whether teriparatide improves fracture healing, more high-quality randomized controlled trials are needed.
PMCID: PMC5173248  PMID: 27997614
29.  Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling 
PLoS ONE  2016;11(12):e0168731.
Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL.
We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children’s Oncology Group (COG) induction therapy from 2014–2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration.
In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone.
Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance.
PMCID: PMC5173249  PMID: 27997622
30.  Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy 
PLoS ONE  2016;11(12):e0168770.
We have recently identified transcription factors (TFs) that are key drivers of breast cancer risk. To better understand the pathways or sub-networks in which these TFs mediate their function we sought to identify upstream modulators of their activity. We applied the MINDy (Modulator Inference by Network Dynamics) algorithm to four TFs (ESR1, FOXA1, GATA3 and SPDEF) that are key drivers of estrogen receptor-positive (ER+) breast cancer risk, as well as cancer progression. Our computational analysis identified over 500 potential modulators. We assayed 189 of these and identified 55 genes with functional characteristics that were consistent with a role as TF modulators. In the future, the identified modulators may be tested as potential therapeutic targets, able to alter the activity of TFs that are critical in the development of breast cancer.
PMCID: PMC5173250  PMID: 27997592
31.  The C-Terminal SynMuv/DdDUF926 Domain Regulates the Function of the N-Terminal Domain of DdNKAP 
PLoS ONE  2016;11(12):e0168617.
NKAP (NF-κB activating protein) is a highly conserved SR (serine/arginine-rich) protein involved in transcriptional control and splicing in mammals. We identified DdNKAP, the Dictyostelium discoideum ortholog of mammalian NKAP, as interacting partner of the nuclear envelope protein SUN-1. DdNKAP harbors a number of basic RDR/RDRS repeats in its N-terminal domain and the SynMuv/DUF926 domain at its C-terminus. We describe a novel and direct interaction between DdNKAP and Prp19 (Pre mRNA processing factor 19) which might be relevant for the observed DdNKAP ubiquitination. Genome wide analysis using cross-linking immunoprecipitation-high-throughput sequencing (CLIP-seq) revealed DdNKAP association with intergenic regions, exons, introns and non-coding RNAs. Ectopic expression of DdNKAP and its domains affects several developmental aspects like stream formation, aggregation, and chemotaxis. We conclude that DdNKAP is a multifunctional protein, which might influence Dictyostelium development through its interaction with RNA and RNA binding proteins. Mutants overexpressing full length DdNKAP and the N-terminal domain alone (DdN-NKAP) showed opposite phenotypes in development and opposite expression profiles of several genes and rRNAs. The observed interaction between DdN-NKAP and the DdDUF926 domain indicates that the DdDUF926 domain acts as negative regulator of the N-terminus.
PMCID: PMC5173251  PMID: 27997579
32.  Signatures of Crested Ibis MHC Revealed by Recombination Screening and Short-Reads Assembly Strategy 
PLoS ONE  2016;11(12):e0168744.
Whole-genome shotgun (WGS) sequencing has become a routine method in genome research over the past decade. However, the assembly of highly polymorphic regions in WGS projects remains a challenge, especially for large genomes. Employing BAC library constructing, PCR screening and Sanger sequencing, traditional strategy is laborious and expensive, which hampers research on polymorphic genomic regions. As one of the most highly polymorphic regions, the major histocompatibility complex (MHC) plays a central role in the adaptive immunity of all jawed vertebrates. In this study, we introduced an efficient procedure based on recombination screening and short-reads assembly. With this procedure, we constructed a high quality 488-kb region of crested ibis MHC that consists of 3 superscaffolds and contains 50 genes. Our sequence showed comparable quality (97.29% identity) to traditional Sanger assembly, while the workload was reduced almost 7 times. Comparative study revealed distinctive features of crested ibis by exhibiting the COL11A2-BLA-BLB-BRD2 cluster and presenting both ADPRH and odorant receptor (OR) gene in the MHC region. Furthermore, the conservation of the BF-TAP1-TAP2 structure in crested ibis and other vertebrate lineages is interesting in light of the hypothesis that coevolution of functionally related genes in the primordial MHC is responsible for the appearance of the antigen presentation pathways at the birth of the adaptive immune system.
PMCID: PMC5173252  PMID: 27997612
33.  The Association between Parameters of Socioeconomic Status and Hypertension in Korea: the Korean Genome and Epidemiology Study 
Journal of Korean Medical Science  2016;31(12):1922-1928.
We investigated the association between socioeconomic status and hypertension in Korea, a country that has experienced a dynamic socioeconomic transition. We analyzed participants of a prospective cohort study—the Korean Genome and Epidemiology Study—enrolled between 2001 and 2003. We recruited 7,089 subjects who underwent a 4-year follow up till 2007. Education and income levels, which are important parameters for socioeconomic status, were stratified into 4 groups. Education level was defined as short (≤ 6 years), mid-short (7–9 years), mid-long (10–12 years), and long (≥ 12 years). Monthly income level was stratified as low (< 500,000 KRW), mid-low (500,000–1,499,999 KRW), mid-high (1,500,000–2,999,999 KRW) or high (≥ 3,000,000 KRW). At baseline, 2,805 subjects (39.5%) were diagnosed with hypertension. Education and income levels were inversely associated with the prevalence and incidence of hypertension (P < 0.001). In multivariate analysis, a shorter duration of education was significantly associated with a higher prevalence of hypertension (P < 0.001), but income level was not (P = 0.305). During the follow-up, 605 subjects (14.2%) were newly diagnosed with hypertension. In multivariate adjusted analysis, the hazard ratios (95% confidence interval) for incident hypertension across the longer education groups were 0.749 (0.544–1.032), 0.639 (0.462–0.884), and 0.583 (0.387–0.879), compared with the shortest education group. There was no significant association between incident hypertension and income across higher income groups: 0.988 (0.714–1.366), 0.780 (0.542–1.121), and 0.693 (0.454–1.056), compared with the lowest income group. In conclusion, education and income levels are associated with the prevalence and incidence of hypertension, but only education is an independent prognostic factor in Korea.
Graphical Abstract
PMCID: PMC5102855  PMID: 27822930
Social Class; Education; Income; Hypertension; Incidence; Prevalence
34.  Clinical Outcomes in Patients with Deferred Coronary Lesions according to Disease Severity Assessed by Fractional Flow Reserve 
Journal of Korean Medical Science  2016;31(12):1929-1936.
Data on the clinical outcomes in deferred coronary lesions according to functional severity have been limited. This study evaluated the clinical outcomes of deferred lesions according to fractional flow reserve (FFR) grade using Korean FFR registry data. Among 1,294 patients and 1,628 lesions in Korean FFR registry, 665 patients with 781 deferred lesions were included in this study. All participants were consecutively categorized into 4 groups according to FFR; group 1: ≥ 0.96 (n = 56), group 2: 0.86–0.95 (n = 330), group 3: 0.81–0.85 (n = 170), and group 4: ≤ 0.80 (n = 99). Primary endpoint was major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction, and target vessel revascularization. The median follow-up period was 2.1 years. During follow-up, the incidence of MACE in groups 1–4 was 1.8%, 7.6%, 8.8%, and 13.1%, respectively. Compared to group 1, the cumulative rate by Kaplan-Meier analysis of MACE was not different for groups 2 and 3. However, group 4 had higher cumulative rate of MACE compared to group 1 (log-rank P = 0.013). In the multivariate Cox hazard models, only FFR (hazard ratio [HR], 0.95; P = 0.005) was independently associated with MACE among all participants. In contrast, previous history of percutaneous coronary intervention (HR, 2.37; P = 0.023) and diagnosis of acute coronary syndrome (ACS) (HR, 2.35; P = 0.015), but not FFR, were independent predictors for MACE in subjects with non-ischemic (FFR ≥ 0.81) deferred coronary lesions. Compared to subjects with ischemic deferred lesions, clinical outcomes in subjects with non-ischemic deferred lesions according to functional severity are favorable. However, longer-term follow-up may be necessary.
Graphical Abstract
PMCID: PMC5102856  PMID: 27822931
Fractional Flow Reserve; Coronary Artery Disease; Prognosis
35.  Antibodies against Hepatitis A and Hepatitis B Virus in Intravenous Immunoglobulin Products 
Journal of Korean Medical Science  2016;31(12):1937-1942.
The worldwide seroprevalence of hepatitis A virus (HAV) and hepatitis B virus (HBV) has changed over the last two decades, indicating a declining incidence of HAV and HBV infections. Therefore, vaccinations against HAV and HBV are recommended for unimmunized people before traveling to an endemic area. Unfortunately, primary antibody deficiency (PAD) patients can only obtain humoral immunity through intravenous immunoglobulin G (IVIG) replacement and not from vaccination because of a defect in antibody production. However, few studies have analyzed the titers of antibodies against HAV or HBV in IVIG products. In this study, the titers of anti-HAV and anti-HBs antibodies were measured in nineteen lots of IVIG products from five manufacturers from three countries (A, B from Korea; C, D from Japan; and E from the USA), and trough titers in plasma were estimated. Concentrations of anti-HAV antibody ranged from 1,888–8,927 mIU/mL and estimated trough titers exceeded the minimal protective value in all evaluated IVIG products. Concentrations of anti-HBs antibody ranged from 438–965 mIU/mL in products A and B and were 157, 123, and 1,945 mIU/mL in products C, D, and E, respectively. Estimated trough titers in products A, B, and E exceeded the minimal protective value but those in products C and D did not reach this threshold. These data demonstrated that available IVIG products generally provide sufficient antibodies against HAV and HBV to protect patients with PAD, although the trough concentrations of anti-HBs antibody in two IVIG products did not reach the minimum protective value.
Graphical Abstract
PMCID: PMC5102857  PMID: 27822932
Antibody; Hepatitis A Virus; Hepatitis B Virus; Intravenous Immunoglobulin
36.  Hemorheological Alteration in Patients Clinically Diagnosed with Chronic Liver Diseases 
Journal of Korean Medical Science  2016;31(12):1943-1948.
Since liver function is changed by chronic liver diseases, chronic liver disease can lead to different hemorheological alterations during the course of the progression. This study aims to compare alterations in whole blood viscosity in patients with chronic liver disease, focusing on the gender effect. Chronic liver diseases were classified into three categories by patient’s history, serologic markers, and radiologic findings: nonalcoholic fatty liver disease (NAFLD) (n = 63), chronic viral hepatitis B and C (n = 50), and liver cirrhosis (LC) (n = 35). Whole blood viscosity was measured by automated scanning capillary tube viscometer, while liver stiffness was measured by transient elastography using FibroScan®. Both systolic and diastolic whole blood viscosities were significantly lower in patients with LC than NAFLD and chronic viral hepatitis (P < 0.001) in male patients, but not in female patients. In correlation analysis, there were inverse relationships between both systolic and diastolic whole blood viscosity and liver stiffness (systolic: r = −0.25, diastolic: r = −0.22). Whole blood viscosity was significantly lower in male patients with LC than NAFLD or chronic viral hepatitis. Our data suggest that whole blood viscosity test can become a useful tool for classifying chronic liver disease and determining the prognosis for different types of chronic liver diseases.
Graphical Abstract
PMCID: PMC5102858  PMID: 27822933
Hemorheology; Whole Blood Viscosity; Chronic Liver Disease
37.  Births to Parents with Asian Origins in the United States, 1992–2012 
Journal of Korean Medical Science  2016;31(12):1949-1956.
Despite a remarkable increase in Asian births in the U.S., studies on their birth outcomes have been lacking. We investigated outcomes of births to Asian parents and biracial Asian/White parents in the U.S. From the U.S. birth data (1992–2012), we selected singleton births to Korean, Chinese, Japanese, Filipino, Asian Indian, and Vietnamese. These births were divided into three groups; births to White mother/Asian father, Asian mother/White father, and births to the both ethnic Asian parents. We compared birth outcomes of these 18 subgroups to those of the White mother/White father group. Mean birthweights of births to the Asian parents were significantly lower, ranging 18 g to 295 g less than to the White parents. Compared to the rates of low birthweight (LBW) (4.6%) and preterm birth (PTB) (8.5%) in births to the White parents, births to Filipino parents had the highest rates of LBW (8.0%) and PTB (11.3%), respectively, and births to Korean parents had the lowest rates of both LBW (3.7%) and PTB (5.5%). This pattern of outcomes had changed little with adjustments of maternal sociodemographic and health factors. This observation was similarly noted also in births to the biracial parents, but the impact of paternal or maternal race on birth outcome was different by race/ethnicity. Compared to births to White parents, birth outcomes from the Asian parents or biracial Asian/White parents differed depending on the ethnic origin of Asian parents. The race/ethnicity was the strongest factor for this difference while other parental characteristics hardly explained this difference.
Graphical Abstract
PMCID: PMC5102859  PMID: 27822934
Asian Americans; Low Birthweight; Preterm Birth
38.  Seroprevalences of Specific IgG Antibodies to Measles, Mumps, and Rubella in Korean Infants 
Journal of Korean Medical Science  2016;31(12):1957-1962.
In this study, the seroprevalences of measles, mumps, and rubella antibodies in infants were determined to assess the immunization strategy and control measures for these infectious diseases. Serum samples from infants < 1 year of age and their mothers were collected to measure the concentrations of specific IgG antibodies to measles, mumps, and rubella by enzyme-linked immunosorbent assay. For selected infant serum samples, measles-specific neutralizing antibody levels were determined by using the plaque reduction neutralization test. The sera from 295 of infants and 80 of their mothers were analyzed. No infants had past measles, mumps, or rubella infections. Almost all infants < 2 months of age were positive for measles and rubella IgG antibodies. However, seroprevalence of measles and rubella antibodies decreased with age, and measles IgG and rubella IgG were barely detectable after 4 months of age. The seroprevalence of mumps antibodies was lower than that of measles and rubella antibodies in infants ≤ 4 months old, and mumps IgG was barely detectable after 2 months of age. The seropositivity of measles-specific neutralizing antibody was 63.6% in infants aged 2 months and undetectable in infants ≥ 6 months old. Because the seropositivity rates of measles, mumps, and rubella antibodies were low after the first few months of age in Korean infants, active immunization with vaccines is strongly recommended for infants aged 6–11 months when measles is epidemic. Timely administration of the first dose of measles-mumps-rubella vaccine at 12 months of age should be encouraged in non-epidemic situations.
Graphical Abstract
PMCID: PMC5102860  PMID: 27822935
Measles; Mumps; Rubella; Seroprevalence; Infant; Korea
39.  Analysis of Malpractice Claims Associated with Surgical Site Infection in the Field of Plastic Surgery 
Journal of Korean Medical Science  2016;31(12):1963-1968.
Postoperative infections are rare after plastic surgery; however, when present, they can affect the aesthetic outcome. Currently, many malpractice lawsuits are associated with surgical site infection. The present study aimed to analyze malpractice claims associated with surgical site infection in the field of plastic surgery through a review of Korean precedents. We analyzed the type of procedure, associated complications, and legal judgment in these cases. Most claimants were women, and claims were most often related to breast surgery. The common complications related to surgical site infection were deformity, scar, and asymmetry. Among the 40 cases, 34 were won by the plaintiff, and the mean claim settlement was 2,832,654 KRW (USD 2,636.6). The reasons for these judgements were as follows: 1) immediate bacterial culture tests were not performed and appropriate antibiotics were not used; 2) patients were not transferred to a high-level hospital or the infection control department was not consulted; 3) surgical site infection control measures were not appropriate; and 4) surgical procedures were performed without preoperative explanation about surgical site infection. The number of claims owing to surgical site infection after surgery is increasing. Infection handling was one of the key factors that influenced the judgement, and preoperative explanation about the possibility of infection is important. The findings will help surgeons achieve high patient satisfaction and reduce liability concerns.
Graphical Abstract
PMCID: PMC5102861  PMID: 27822936
Nosocomial Infection; Plastic Surgery; Malpractice Litigation; Surgical Site Infection
40.  Development and Validation of the Korean Version of Hand-Foot Skin Reaction and Quality of Life Questionnaire (HF-QoL-K) 
Journal of Korean Medical Science  2016;31(12):1969-1975.
Given the growing number of cancer patients and the resulting increase in the administration of chemotherapeutic agents, convenient and effective methods for measuring the symptoms and quality of life associated with the hand-foot syndrome (HFS) are needed. Therefore, the aim of this study was to develop and validate the Korean version of the hand-foot skin reaction and quality of life questionnaire (HF-QoL-K), comprising a 20-item symptom domain and an 18-item daily activity domain. After we developed the HF-QoL-K, 209 Korean patients with gynecologic cancer who were undergoing chemotherapeutic agents relating the HFS were asked to fill in the questionnaire. The content validity, internal consistency reliability, and test-retest reliability were evaluated. The internal validity index, Cronbach’s alpha coefficient, and intra-class correlation coefficient of the HF-QoL-K were 0.90, 0.958, and 0.825 (95% confidence interval [CI], 0.774–0.865), respectively. The scatter plot (Pearson correlation coefficient, 0.826) and the Bland-Altman plot for test-retest reliability were also acceptable. The HF-QoL-K instrument is a valid and reliable questionnaire for the measurement of the symptoms and quality of life in Korean cancer patients suffering HFS.
Graphical Abstract
PMCID: PMC5102862  PMID: 27822937
Hand-Foot Syndrome; Quality of Life; Questionnaires; Validation; Gynecologic Cancer; Chemotherapy
41.  Impact of Young Age at Diagnosis on Survival in Patients with Surgically Treated Renal Cell Carcinoma: a Multicenter Study 
Journal of Korean Medical Science  2016;31(12):1976-1982.
The prognostic significance of age in renal cell carcinoma (RCC) is a subject of debate. The aim of the present multi-institutional study was to evaluate the impact of age on clinicopathological features and survival in a large cohort of patients with RCC. A total of 5,178 patients who underwent surgery for RCC at eight institutions in Korea between 1999 and 2011 were categorized into three groups according to age at diagnosis as follows: young age (< 40 years, n = 541), middle-age (≥ 40 and < 60 years, n = 2,551), and old age (≥ 60 years, n = 2,096) groups. Clinicopathological variables and survival rates were compared between the three groups. Young patients had lower stage tumors with a low Fuhrman grade, a lower rate of lymphovascular invasion than patients in the other age groups. Regarding histologic type, the young age group had a lower percentage of clear cell histology and a greater incidence of Xp11.2 translocation RCC. Kaplan-Meier estimates showed that cancer-specific survival was significantly better in the young age group than in the other groups (log rank test, P = 0.008). However, age at diagnosis was not an independent predictor of survival in multivariate analysis. In conclusion, young age at diagnosis was associated with favorable pathologic features, although it was not an independent prognostic factor for survival in patients with surgically-treated RCC. Age itself should not be regarded as a crucial determinant for the treatment of RCC.
Graphical Abstract
PMCID: PMC5102863  PMID: 27822938
Renal Cell Carcinoma; Nephrectomy; Age; Recurrence; Survival
43.  PET imaging of T cells derived from umbilical cord blood 
Leukemia  2008;23(3):620-622.
PMCID: PMC5108177  PMID: 18830258
44.  Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells 
Cell reports  2016;17(3):821-836.
Metabolic reprogramming is critical to oncogenesis, but the emergence and function of this profound reorganization remain poorly understood. Here we find that cooperating oncogenic mutations drive large-scale metabolic reprogramming, which is both intrinsic to cancer cells and obligatory for the transition to malignancy. This involves synergistic regulation of several genes encoding metabolic enzymes, including the lactate dehydrogenases LDHA and LDHB and mitochondrial glutamic pyruvate transaminase 2 (GPT2). Notably, GPT2 engages activated glycolysis to drive the utilization of glutamine as a carbon source for TCA cycle anaplerosis in colon cancer cells. Our data indicate that the Warburg effect supports oncogenesis via GPT2-mediated coupling of pyruvate production to glutamine catabolism. Although critical to the cancer phenotype, GPT2 activity is dispensable in cells that are not fully transformed, thus pinpointing a metabolic vulnerability specifically associated with cancer cell progression to malignancy.
Graphical Abstract
PMCID: PMC5108179  PMID: 27732857
45.  Issue Information 
Evolutionary Applications  2016;9(10):1203-1204.
PMCID: PMC5108212
46.  Vitamin D, Fibroblast Growth Factor 23 and Incident Cognitive Impairment: Findings from the REGARDS Study 
PLoS ONE  2016;11(11):e0165671.
Vitamin D protects against cognitive decline in animals but evidence in humans has been inconsistent. Fibroblast growth factor 23 (FGF23) is a hormone that inhibits vitamin D activation yet few studies examined whether FGF23 is associated with cognitive impairment. The objective of this study was to examine associations of 25(OH)D and FGF23 with incident cognitive impairment in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years old. FGF23 and 25(OH)D were measured in 474 incident impairment cases and 561 controls. In multivariable-adjusted models, there were no significant associations of FGF23 with incident cognitive impairment. In analyses using clinically-relevant categories of 25(OH)D (< 20 ng/ml, 20–29.9 ng/ml, ≥30 ng/ml), there was no statistically significant association of lower 25(OH)D concentrations with odds of incident cognitive impairment in models adjusted for demographic, clinical, and laboratory variables and season of blood draw (tertile 1 [≥30 ng/ml] reference; tertile 2 [20–29.9 ng/ml], odds ratio [OR] 0.96, 95%CI 0.67, 1.38; tertile 3 [<20 ng/ml] OR 1.26, 95%CI 0.83, 1.91). When 25(OH)D was modeled as race-specific tertiles, there were no significant associations of 25(OH)D with incident cognitive impairment in whites, whereas lower 25(OH)D was associated with higher odds in blacks (tertile 1 [>23 ng/ml] reference; tertile 2 [15–23 ng/ml], OR 2.96, 95%CI 1.48,5.94; tertile 3 [<15 ng/ml] OR 2.40, 95%CI 1.07,5.40) in the fully adjusted model. In this cohort of older adults, lower race-specific tertiles of 25(OH)D were associated with higher incidence of cognitive impairment in black individuals but not white individuals. These data suggest that treating low 25(OH)D may be a novel strategy for addressing racial disparities in neurocognitive outcomes.
PMCID: PMC5094718  PMID: 27812184
47.  Evolution of normal and neoplastic tissue stem cells: progress after Robert Hooke 
The appearance of stem cells coincides with the transition from single-celled organisms to metazoans. Stem cells are capable of self-renewal as well as differentiation. Each tissue is maintained by self-renewing tissue-specific stem cells. The accumulation of mutations that lead to preleukaemia are in the blood-forming stem cell, while the transition to leukaemia stem cells occurs in the clone at a progenitor stage. All leukaemia and cancer cells escape being removed by scavenger macrophages by expressing the 'don't eat me' signal CD47. Blocking antibodies to CD47 are therapeutics for all cancers, and are currently being tested in clinical trials in the US and UK.
PMCID: PMC4633993  PMID: 26416675
stem cell; leukaemia; cancer; neoplasm; competition
48.  Somatic cell nuclear transfer: origins, the present position and future opportunities 
Nuclear transfer that involves the transfer of the nucleus from a donor cell into an oocyte or early embryo from which the chromosomes have been removed was considered first as a means of assessing changes during development in the ability of the nucleus to control development. In mammals, development of embryos produced by nuclear transfer depends upon coordination of the cell cycles of donor and recipient cells. Our analysis of nuclear potential was completed in 1996 when a nucleus from an adult ewe mammary gland cell controlled development to term of Dolly the sheep. The new procedure has been used to target the first precise genetic modification into livestock; however, the greatest inheritance of the Dolly experiment was to make biologists think differently. If unknown factors in the recipient oocyte could reprogramme the nucleus to a stage very early in development then there must be other ways of making that change. Within 10 years, two laboratories working independently established protocols by which the introduction of selected transcription factors changes a small proportion of the treated cells to pluripotent stem cells. This ability to produce ‘induced pluripotent stem cells’ is providing revolutionary new opportunities in research and cell therapy.
PMCID: PMC4633995  PMID: 26416677
nuclear transfer; cell cycle; reprogramming; Dolly the sheep; iPS cells; disease models
49.  Direct somatic lineage conversion 
The predominant view of embryonic development and cell differentiation has been that rigid and even irreversible epigenetic marks are laid down along the path of cell specialization ensuring the proper silencing of unrelated lineage programmes. This model made the prediction that specialized cell types are stable and cannot be redirected into other lineages. Accordingly, early attempts to change the identity of somatic cells had little success and was limited to conversions between closely related cell types. Nuclear transplantation experiments demonstrated, however, that specialized cells even from adult mammals can be reprogrammed into a totipotent state. The discovery that a small combination of transcription factors can reprogramme cells to pluripotency without the need of oocytes further supported the view that these epigenetic barriers can be overcome much easier than assumed, but the extent of this flexibility was still unclear. When we showed that a differentiated mesodermal cell can be directly converted to a differentiated ectodermal cell without a pluripotent intermediate, it was suggested that in principle any cell type could be converted into any other cell type. Indeed, the work of several groups in recent years has provided many more examples of direct somatic lineage conversions. Today, the question is not anymore whether a specific cell type can be generated by direct reprogramming but how it can be induced.
PMCID: PMC4633997  PMID: 26416679
cell fate conversion; direct reprogramming; induced neuronal cells; induced pluripotent stem cells; pluripotent stem cell-derived induced neuronal cells
50.  From gristle to chondrocyte transplantation: treatment of cartilage injuries 
This review addresses the progress in cartilage repair technology over the decades with an emphasis on cartilage regeneration with cell therapy. The most abundant cartilage is the hyaline cartilage that covers the surface of our joints and, due to avascularity, this tissue is unable to repair itself. The cartilage degeneration seen in osteoarthritis causes patient suffering and is a huge burden to society. The surgical approach to cartilage repair was non-existing until the 1950s when new surgical techniques emerged. The use of cultured cells for cell therapy started as experimental studies in the 1970s that developed over the years to a clinical application in 1994 with the introduction of the autologous chondrocyte transplantation technique (ACT). The technology is now spread worldwide and has been further refined by combining arthroscopic techniques with cells cultured on matrix (MACI technology). The non-regenerating hypothesis of cartilage has been revisited and we are now able to demonstrate cell divisions and presence of stem-cell niches in the joint. Furthermore, cartilage derived from human embryonic stem cells and induced pluripotent stem cells could be the base for new broader cell treatments for cartilage injuries and the future technology base for prevention and cure of osteoarthritis.
PMCID: PMC4633998  PMID: 26416680
cartilage; stem cells; cell therapy

Results 26-50 (2588)