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1.  Single monosomy as a relatively better survival factor in acute myeloid leukemia patients with monosomal karyotype 
Blood Cancer Journal  2015;5(10):e358-.
Monosomal karyotype (MK) defined by either ⩾2 autosomal monosomies or single monosomy with at least one additional structural chromosomal abnormality is associated with a dismal prognosis in patients with acute myeloid leukemia (AML). It was detected in 174 of 3041 AML patients in South Korean Registry. A total of 119 patients who had received induction therapy were finally analyzed to evaluate the predictive factors for a positive prognosis. On multivariate analysis, single monosomy, the absence of abn(17p), ⩾10% of cells with normal metaphase and the achievement of a complete remission (CR) after induction therapy were significant factors for more favorable outcomes. Especially, single monosomy remained as a significantly independent prognostic factor for superior survival in both patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR and who did not. Allo-HSCT in CR improved overall survival significantly only in patients with a single monosomy. Our results suggest that MK-AML may be biologically different according to the karyotypic subtype and that allo-HSCT in CR should be strongly recommended to patients with a single monosomy. For other patients, more prudent treatment strategies should be examined. Furthermore, the biological mechanism by which a single monosomy influences survival should be investigated.
doi:10.1038/bcj.2015.84
PMCID: PMC4635193  PMID: 26473530
2.  High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia 
British Journal of Cancer  2012;107(1):108-115.
Background:
Cytosine arabinoside-based chemotherapy coupled with anthracycline is currently the first-line treatment for acute myeloid leukaemia (AML), but diverse responses to the regimen constitute obstacles to successful treatment. Therefore, outcome prediction to chemotherapy at diagnosis is believed to be a critical consideration.
Methods:
The mRNA expression of 12 genes closely involved in the actions of cytosine arabinoside and anthracycline was evaluated by real-time reverse transcriptase PCR (RT–PCR), in 54 diagnostic bone marrow specimens of M2-subtype AML.
Results:
Low expression levels of ribonucleotide reductase M2 (RRM2) and high expression levels of topoisomerase 2 beta (TOP2B) were correlated with longer survival in a univariate analysis. Another interesting finding is that high ratios of TOP2B/RRM2 and TOP2B/TOP2 alpha (TOP2A) in a combined analysis were also shown to have a prognostic impact for longer survival with improved accuracy. Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005).
Conclusion:
Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype.
doi:10.1038/bjc.2012.206
PMCID: PMC3389410  PMID: 22627319
AML; standard chemotherapy; prognosis; topoisomerase 2
3.  Effects of Ambient Temperature on Growth Performance, Blood Metabolites, and Immune Cell Populations in Korean Cattle Steers 
Exposure to cold may affect growth performance in accordance with the metabolic and immunological activities of animals. We evaluated whether ambient temperature affects growth performance, blood metabolites, and immune cell populations in Korean cattle. Eighteen Korean cattle steers with a mean age of 10 months and a mean weight of 277 kg were used. All steers were fed a growing stage-concentrate diet at a rate of 1.5% of body weight and Timothy hay ad libitum for 8 weeks. Experimental period 1 (P1) was for four weeks from March 7 to April 3 and period 2 (P2) was four weeks from April 4 to May 1. Mean (8.7°C) and minimum (1.0°C) indoor ambient temperatures during P1 were lower (p<0.001) than those (13.0°C and 6.2°C, respectively) during P2. Daily dry matter feed intake in both the concentrate diet and forage groups was higher (p<0.001) during P2 than P1. Average daily weight gain was higher (p<0.001) during P2 (1.38 kg/d) than P1 (1.13 kg/d). Feed efficiency during P2 was higher (p = 0.015) than P1. Blood was collected three times; on March 7, April 4, and May 2. Nonesterified fatty acids (NEFA) were higher on March 7 than April 4 and May 2. Blood cortisol, glucose, and triglyceride concentrations did not differ among months. Blood CD4+, CD8+, and CD4+CD25+ T cell percentages were higher, while CD8+CD25+ T cell percentage was lower, during the colder month of March than during May, suggesting that ambient temperature affects blood T cell populations. In conclusion, colder ambient temperature decreased growth and feed efficiency in Korean cattle steers. The higher circulating NEFA concentrations observed in March compared to April suggest that lipolysis may occur at colder ambient temperatures to generate heat and maintain body temperature, resulting in lower feed efficiency in March.
doi:10.5713/ajas.15.0937
PMCID: PMC4811797  PMID: 26950877
Korean Cattle; Ambient Temperature; Growth; Feed Efficiency; Blood Metabolites; Immune Cells
4.  Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer 
British Journal of Cancer  2014;112(1):103-111.
Background:
Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance.
Methods:
We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.
Results:
Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting.
Conclusions:
Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.
doi:10.1038/bjc.2014.556
PMCID: PMC4453607  PMID: 25349977
breast carcinoma; gene amplification; EGFR; HER2; trastuzumab; immunohistochemistry
5.  Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures 
Cell Death and Differentiation  2014;21(7):1095-1106.
Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood–brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote (+/−) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP (+/−) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP (+/−) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-κB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.
doi:10.1038/cdd.2014.29
PMCID: PMC4207478  PMID: 24608792
6.  Manipulation of a quasi-natural cell block for high-efficiency transplantation of adherent somatic cells 
Recent advances have raised hope that transplantation of adherent somatic cells could provide dramatic new therapies for various diseases. However, current methods for transplanting adherent somatic cells are not efficient enough for therapeutic applications. Here, we report the development of a novel method to generate quasi-natural cell blocks for high-efficiency transplantation of adherent somatic cells. The blocks were created by providing a unique environment in which cultured cells generated their own extracellular matrix. Initially, stromal cells isolated from mice were expanded in vitro in liquid cell culture medium followed by transferring the cells into a hydrogel shell. After incubation for 1 day with mechanical agitation, the encapsulated cell mass was perforated with a thin needle and then incubated for an additional 6 days to form a quasi-natural cell block. Allograft transplantation of the cell block into C57BL/6 mice resulted in perfect adaptation of the allograft and complete integration into the tissue of the recipient. This method could be widely applied for repairing damaged cells or tissues, stem cell transplantation, ex vivo gene therapy, or plastic surgery.
doi:10.1590/1414-431X20144322
PMCID: PMC4445661  PMID: 25742639
Quasi-natural cell block; Transplantation; Scaffold; Extracellular matrix; Hydrogel
7.  Tuberculosis before hematopoietic stem cell transplantation in patients with hematologic diseases: report of a single-center experience 
Transplant Infectious Disease  2015;17(1):73-79.
Background
Few reports discuss the optimal management of patients diagnosed with tuberculosis (TB) before scheduled stem cell transplantation (SCT), who then proceed with transplantation.
Methods
We found 13 patients with TB before SCT (proven, n = 9; probable, n = 3; possible, n = 1) in the medical records of our institution.
Results
Most of the patients had pulmonary TB (n = 8; disseminated, n = 2; extrapulmonary, n = 3). Eight of 9 patients with proven disease had SCT after at least 100 days of anti-tuberculous medication, ranging from 103 to 450 days. None of those patients suffered TB-related events after SCT. However, 1 patient with proven pulmonary TB who underwent SCT after only 40 days of anti-tuberculous therapy subsequently died of TB meningitis. Patients with possible and probable disease had their transplants after 6–176 days of anti-tuberculous medication, and all were alive at the time of analysis. The entire duration of anti-tuberculous medication was 12 months in most cases. With a follow-up duration ranging from 0.7 to 87.5 months, 4 patients died, but TB was the cause of death in only 1 case.
Conclusion
In conclusion, for proven cases of TB, SCT after >100 days of anti-tuberculous medication is probably feasible and safe, in terms of TB control, in patients with various hematologic diseases.
doi:10.1111/tid.12341
PMCID: PMC4345421  PMID: 25620389
tuberculosis; hematologic diseases; stem cell transplantation
8.  Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer 
British Journal of Cancer  2013;109(10):2705-2713.
Background:
Tumour-infiltrating lymphocytes (TILs) are known to be associated with response to primary systemic therapy (PST) in breast cancer. This study was conducted to assess the association of TIL subsets with pathological complete response (pCR) after PST in breast cancer in relation to breast cancer subtype, breast cancer stem cell (BCSC) phenotype and epithelial–mesenchymal transition (EMT).
Methods:
The pre-chemotherapeutic biopsy specimens of 153 breast cancer patients who underwent surgical resection after anthracycline- or anthracycline/taxane-based PST were analysed. TIL subsets (CD4+, CD8+, and FOXP3+ TILs), BCSC phenotype, and the expression of EMT markers were evaluated by immunohistochemistry and were correlated with pCR after PST.
Results:
Infiltration of CD4+ and CD8+ T lymphocytes was closely correlated with BCSC phenotype and EMT. High levels of CD4+, CD8+, and FOXP3+ TILs were associated with pCR, and CD8+ TILs were found to be an independent predictive factor for pCR. In addition, CD8+ TILs were associated with pCR irrespective of breast cancer subtype, CD44+/CD24− phenotype, EMT, and chemotherapeutic regimen in subgroup analyses.
Conclusion:
These findings indicate that CD8+ cytotoxic T lymphocytes are a key component of TILs associated with chemo-response and can be used as a reliable predictor of response to anthracycline- or anthracycline/taxane-based PST in breast cancer.
doi:10.1038/bjc.2013.634
PMCID: PMC3833219  PMID: 24129232
primary systemic therapy; pathological complete response; tumour-infiltrating lymphocytes; CD8; cytotoxic T lymphocyte
9.  The effect of resveratrol on normal and osteoarthritic chondrocyte metabolism 
Bone & Joint Research  2014;3(3):51-59.
Background
Resveratrol is a polyphenolic compound commonly found in the skins of red grapes. Sirtuin 1 (SIRT1) is a human gene that is activated by resveratrol and has been shown to promote longevity and boost mitochondrial metabolism. We examined the effect of resveratrol on normal and osteoarthritic (OA) human chondrocytes.
Methods
Normal and OA chondrocytes were incubated with various concentrations of resveratrol (1 µM, 10 µM, 25 µM and 50 µM) and cultured for 24, 48 or 72 hours or for six weeks. Cell proliferation, gene expression, and senescence were evaluated.
Results
SIRT1 was significantly upregulated in normal chondrocytes with resveratrol concentrations of 25 µM and 50 µM on both two- (2D) (both p = 0.001) and three-dimensional (3D) cultures (p = 0.008 and 0.001, respectively). It was significantly upregulated in OA chondrocytes treated with 10 µM, 25 µM and 50 µM resveratrol on 2D cultures (p = 0.036, 0.002 and 0.001, respectively) and at 50 µM concentration on 3D cultures (p = 0.001). At 72 hours, the expression of collagen (COL)-10, aggrecan (AGG), and runt-related transcription factor 2 (RUNX2) was significantly greater in both 25 µM (p = 0.011, 0.006 and 0.015, respectively) and 50 µM (p = 0.019, 0.004 and 0.002, respectively) resveratrol-treated normal chondrocyte cultures. In OA chondrocytes, expression of COL10 and RUNX2 was significantly greater in 25 µM (p = 0.004 and 0.024) and 50 µM (p = 0.004 and 0.019) cultures at 72 hours on 3D cultures.
Conclusions
At concentrations of 25 µM and/or 50 µM, resveratrol treatment significantly upregulates SIRT1 gene expression in normal and osteoarthritic chondrocytes. Resveratrol induces chondrocytes into a hypertrophic state through upregulation of COL1, COL10, and RUNX2.
Cite this article: Bone Joint Res 2014;3:51–9.
doi:10.1302/2046-3758.33.2000226
PMCID: PMC3963380  PMID: 24615710
Resveratrol; SIRT1; Osteoarthritis; Chondrocyte; Longevity; Metabolism
10.  Correlation of the apparent diffusion coefficiency values on diffusion-weighted imaging with prognostic factors for breast cancer 
The British Journal of Radiology  2012;85(1016):e474-e479.
Objective
The aim of this study was to correlate the apparent diffusion coefficient (ADC) value of breast cancer with prognostic factors.
Methods
335 patients with invasive ductal carcinoma not otherwise specified (IDC NOS) and ductal carcinoma in situ (DCIS) who underwent breast MRI with diffusion-weighted imaging were included in this study. ADC of breast cancer was calculated using two b factors (0 and 1000 s mm–2). Mean ADCs of IDC NOS and DCIS were compared and evaluated. Among cases of IDC NOS, mean ADCs were compared with lymph node status, size and immunochemical prognostic factors using Student's t-test. ADC was also correlated with histological grade using the Kruskal–Wallis test.
Results
Mean ADC of IDC NOS was significantly lower than that of DCIS (p<0.001). However, the mean ADC of histological grade of IDC NOS was not significantly different (p=0.564). Mean ADC of oestrogen receptor (ER)-positive or progesterone receptor (PR)-positive cancer was significantly lower than that of ER-negative or PR-negative cancer (p=0.003 vs p=0.032). Mean ADC of Ki-67 index-positive cancer was significantly lower than that of Ki-67 index-negative cancer (p=0.028). Mean ADC values of cancers with increased microvascular density (MVD) were significantly lower than those of cancer with no MVD increase (p=0.009). No correlations were observed between mean ADC value and human growth factor receptor 2 expression, tumour size and lymph node metastasis.
Conclusion
Low ADC value was correlated with positive expression of ER, PR, increased Ki-67 index, and increased MVD of breast cancer.
doi:10.1259/bjr/79381464
PMCID: PMC3587081  PMID: 22128125
11.  BRCA1 negatively regulates IGF-1 expression through an estrogen-responsive element-like site 
Cell Death & Disease  2012;3(6):e336-.
The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is critical for both normal mammary gland development and malignant transformation. It has been reported that the IGF-1 stimulates breast cancer cell proliferation and is upregulated in tumors with BRCA1/2 mutations. We report here that IGF-1 is negatively regulated by BRCA1 at the transcriptional level in human breast cancer cells. BRCA1 knockdown (BRCA1-KD) induces the expression of IGF-1 mRNA in MCF7 cells in an estrogen receptor α (ERα)-dependent manner. We found that both BRCA1 and ERα bind to the endogenous IGF-1 promoter region containing an estrogen-responsive element-like (EREL) site. BRCA1-KD does not significantly affect ERα binding on the IGF-1 promoter. Reporter analysis demonstrates that BRCA1 could regulate IGF-1 transcripts via this EREL site. In addition, enzyme-linked immunosorbent assay revealed that de-repression of IGF-1 transcription by BRCA1-KD increases the level of extracellular IGF-1 protein, and secreted IGF-1 seems to increase the phospho-IGF-1Rβ and activate its downstream signaling pathway. Blocking the IGF-1/IGF-1R/phosphoinositide 3-kinase (PI3K)/AKT pathway either by a neutralizing antibody or by small-molecule inhibitors preferentially reduces the proliferation of BRCA1-KD cells. Furthermore, the IGF-1-EREL-Luc reporter assay demonstrates that various inhibitors, which can inhibit the IGF-1R pathway, can suppress this reporter activity. These findings suggest that BRCA1 defectiveness keeps turning on IGF-1/PI3K/AKT signaling, which significantly contributes to increase cell survival and proliferation.
doi:10.1038/cddis.2012.78
PMCID: PMC3388245  PMID: 22739988
BRCA1; IGF-1; negative regulation; ERα; positive-feedback activation
12.  c-Myc expression is related with cell proliferation and associated with poor clinical outcome in human gastric cancer. 
Journal of Korean Medical Science  1999;14(5):526-530.
We underwent protein assay for Myc expression in 76 human gastric cancer tissues using immunohistochemistry. Expression of Myc protein was analyzed according to proliferative indices measured by flow cytometry. Levels of Myc protein expression was evaluated by correlating with biologic and clinical parameters. In 36 (47.4%) of 76 primary gastric cancers, overexpression of Myc was observed. We could observe expression of Myc protein in a significant portion of early gastric cancer (42.9%). Expression of Myc protein was demonstrated to be more frequent in poorly differentiated cancer cells (p=0.043). However, expression of Myc protein had little influence over progress or extent of the disease. Expression of Myc protein was significantly correlated with increased proliferative activity (p=0.032) and patients with high levels of Myc expression had poor disease-free survival. In a certain proportion of human gastric cancer, Myc protein may function as a regulator of cancer cell growth and expression of Myc may represent an aggressive phenotype of gastric cancer.
PMCID: PMC3054460  PMID: 10576148
13.  The first imported case of pulmonary coccidioidomycosis in Korea. 
Journal of Korean Medical Science  1999;14(2):206-209.
Coccidioidomycosis is an endemic disease found in the southwestern part of North America. Travellers who visit the endemic area may carry the infection. We report a case of pulmonary coccidioidomycosis in a 74-year-old woman. She was healthy before visiting Arizona, U.S.A twice. After returning home, she began to complain of intermittent dry coughing. The symptom was mild, however, and she was treated symptomatically. Later a chest radiograph, which was taken 4 years after the onset of the symptom, showed a solitary pulmonary nodule in the right upper lobe. By percutaneous needle aspiration, a few clusters of atypical cells were noted in the necrotic background. A right upper and middle lobectomy was done. A 1.5 x 1.5 x 1.2 cm sized tan nodule was present in otherwise normal lung parenchyma. Microscopically, the nodule consisted of aggregates of multiple solid granulomas inside of which was mostly necrotic. Neutrophils and nuclear debris were scattered along the periphery of the necrotic foci. Numerous multinucleated giant cells were associated with the granulomas. In the necrotic area, mature spherules of Coccidioides immitis, which were 30-100 microm in diameter, were present. They contained numerous endospores which ranged from 5 to 15 microm and were also noted in multinucleated giant cells. The diagnosis of coccidioidomycosis was made. She is doing well after the resection.
PMCID: PMC3054355  PMID: 10331569
14.  Mixed hepatoblastoma in an adult--a case report and literature review. 
Journal of Korean Medical Science  1997;12(4):369-373.
Hepatoblastoma is thought to originate from embryonal hepatic tissue, and most of these tumors occur in children under the age of 2 years. Hepatoblastoma in adults is extremely rare, and the prognosis is much worse than the mixed hepatoblastoma of childhood. We experienced a case of mixed hepatoblastoma in a 51 year old female patient. She had been suffering from a mild pain and a palpable lump in the epigastric area. Serum AFP was 43,850 ng/ml. Computerized tomography and selective abdominal angiography showed a large low-density mass. With a suspicion of hepatocellular carcinoma of the left lobe, a left lateral segmentectomy was performed. The external surface showed a huge protruding mass and the capsule was previously ruptured. On section, the tumor was a 11 x 7 cm sized expanding mass which had a variegated surface composed of yellow-white friable tissue with multifocal hemorrhagic areas. Microscopic examination revealed a tumor consisted of epithelial and mesenchymal elements. The mesenchymal cells were spindle in shape and proliferated over the whole tumor with focal osteosarcomatous differentiation. The epithelial components showed well-differentiated hepatocellular carcinoma-like areas, poorly differentiated acinar or tubular structures.
PMCID: PMC3054210  PMID: 9288639
15.  Spinal congenital dermal sinus--experience of 5 cases over a period of 10 years. 
Spinal congenital dermal sinus (CDS) is a rare entity which supposedly results from the failure of the neuroectoderm to separate from the cutaneous ectoderm during the process of neurulation. The lesions are most frequent at the lumbosacral followed by the occipital region. CDS of the thoracic region is very rare. The patients with spinal CDS present with meningitis and/or mass effect from the associated inclusion tumor. They are usually dermoid or epidermoid cysts. Teratoma is rarely associated. The authors experienced 5 cases of spinal CDS over a 10 year period. Of the 5 cases, 2 were at thoracic and 3 were at lumbosacral levels. Dermoid cyst, epidermoid cyst and teratoma were associated in one case each. Two cases presented with neurological deficit and meningitis while an additional case presented with neurological deficit and a history of probable meningitis. Pain was present in 2 cases. Magnetic resonance imaging played an important role in the diagnosis of the lesion and planning of surgery. All the cases showed a good response to surgery even though one patient had persistent neurological deficit.
PMCID: PMC3053715  PMID: 8305142
16.  Variability in CT lung-nodule quantification: Effects of dose reduction and reconstruction methods on density and texture based features 
Medical Physics  2016;43(8):4854-4865.
Purpose:
To investigate the effects of dose level and reconstruction method on density and texture based features computed from CT lung nodules.
Methods:
This study had two major components. In the first component, a uniform water phantom was scanned at three dose levels and images were reconstructed using four conventional filtered backprojection (FBP) and four iterative reconstruction (IR) methods for a total of 24 different combinations of acquisition and reconstruction conditions. In the second component, raw projection (sinogram) data were obtained for 33 lung nodules from patients scanned as a part of their clinical practice, where low dose acquisitions were simulated by adding noise to sinograms acquired at clinical dose levels (a total of four dose levels) and reconstructed using one FBP kernel and two IR kernels for a total of 12 conditions. For the water phantom, spherical regions of interest (ROIs) were created at multiple locations within the water phantom on one reference image obtained at a reference condition. For the lung nodule cases, the ROI of each nodule was contoured semiautomatically (with manual editing) from images obtained at a reference condition. All ROIs were applied to their corresponding images reconstructed at different conditions. For 17 of the nodule cases, repeat contours were performed to assess repeatability. Histogram (eight features) and gray level co-occurrence matrix (GLCM) based texture features (34 features) were computed for all ROIs. For the lung nodule cases, the reference condition was selected to be 100% of clinical dose with FBP reconstruction using the B45f kernel; feature values calculated from other conditions were compared to this reference condition. A measure was introduced, which the authors refer to as Q, to assess the stability of features across different conditions, which is defined as the ratio of reproducibility (across conditions) to repeatability (across repeat contours) of each feature.
Results:
The water phantom results demonstrated substantial variability among feature values calculated across conditions, with the exception of histogram mean. Features calculated from lung nodules demonstrated similar results with histogram mean as the most robust feature (Q ≤ 1), having a mean and standard deviation Q of 0.37 and 0.22, respectively. Surprisingly, histogram standard deviation and variance features were also quite robust. Some GLCM features were also quite robust across conditions, namely, diff. variance, sum variance, sum average, variance, and mean. Except for histogram mean, all features have a Q of larger than one in at least one of the 3% dose level conditions.
Conclusions:
As expected, the histogram mean is the most robust feature in their study. The effects of acquisition and reconstruction conditions on GLCM features vary widely, though trending toward features involving summation of product between intensities and probabilities being more robust, barring a few exceptions. Overall, care should be taken into account for variation in density and texture features if a variety of dose and reconstruction conditions are used for the quantification of lung nodules in CT, otherwise changes in quantification results may be more reflective of changes due to acquisition and reconstruction conditions than in the nodule itself.
doi:10.1118/1.4954845
PMCID: PMC4967078  PMID: 27487903
computed tomography; texture; dose; reconstruction kernel; lung nodule; radiomics
17.  Laughter and Stress Relief in Cancer Patients: A Pilot Study 
The purpose of this study was to examine the effect of a therapeutic laughter program and the number of program sessions on anxiety, depression, and stress in breast cancer patients. A randomized controlled trial was conducted involving 31 patients who received four sessions of therapeutic laughter program comprised and 29 who were assigned to the no-program control group. Scores for anxiety, depression, and stress were measured using an 11-point numerical rating scale. While no change was detected in the control group, the program group reported reductions of 1.94, 1.84, and 2.06 points for anxiety, depression, and stress, respectively (p < 0.01, p < 0.01, and p < 0.01). Scores decreased significantly after the first therapeutic laughter session (p < 0.05, p < 0.01, and p < 0.01). As the therapeutic laughter program was effective after only a single session in reducing anxiety, depression, and stress in breast cancer patients, it could be recommended as a first-line complementary/alternative therapy.
doi:10.1155/2015/864739
PMCID: PMC4439472  PMID: 26064177
18.  Significance of KIT exon 17 mutation depends on mutant level rather than positivity in core-binding factor acute myeloid leukemia 
Blood Cancer Journal  2016;6(1):e387-.
KIT exon 17 mutation is a poor prognostic factor in core-binding factor acute myeloid leukemia. However, the mutation detection method used for risk assessment is not assigned. It is necessary to verify the analytical and clinical performance before applying new methods. Herein, we firstly applied a highly sensitive allele-specific, real-time quantitative PCR (AS-qPCR) assay to analyze KIT mutations, which demonstrated excellent sensitivity and specificity. Much higher incidence of KIT mutations (62.2%, 69/111) and prevalence of multiple mutations (43.5%, 30/69) were observed using AS-qPCR, which meant the existence of multiple KIT mutant subclones. The relative KIT mutant level was variable (median, 0.3 per control allele 100 copies, 0.002–532.7) and was divided into two groups: high (⩾10, n=26) and low (<10) mutant level. Interestingly, rather than mutation positivity, mutant level was found to be associated with clinical outcome. High mutant level showed significantly inferior overall survival (P=0.005) and event-free survival (P=0.03), whereas low level did not influence the prognosis. The follow-up data showed that the mutant level were along with fusion transcripts in the majority (n=29), but moved separately in some cases, including the loss of mutations (n=5) and selective proliferation of minor clones (n=2) at relapse. This study highlighted that the KIT mutation should be analyzed using sensitive and quantitative techniques and set a cutoff level for identifying the risk group.
doi:10.1038/bcj.2015.116
PMCID: PMC4742633  PMID: 26771813
19.  Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length 
Blood Cancer Journal  2015;5(8):e336-.
Mutation of the fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), which is one of the most frequent genetic alterations, strongly contributes to an increased risk of treatment failure and to poor prognosis. In this study, we established quantitative fragment analysis of FLT3-ITD simultaneously measuring mutant allele burden and length, verified the analytical performance and evaluated the clinical significance in adult acute myeloid leukemia (AML) patients. FLT3-ITD was detected in 73 of 363 adult AML patients (20.1%) and high mutant allelic burden (⩾50%, n=13) and long ITD length (⩾70 base pairs, n=15) were significantly associated with inferior overall survival (OS; P=0.002 and 0.005, respectively) and event-free survival (EFS; P=0.004 and 0.007, respectively). FLT3-ITD poor prognostic group was identified as patients with high allele burden or long ITD length (n=24), which revealed significant adverse clinical outcome for both OS (P<0.001) and EFS (P<0.001). In cytogenetically normal AML, even FLT3-ITD low allele burden and short length was associated with poorer OS (P=0.037) and EFS (P=0.044) than wild type, whose influence was overcome when hematopoietic stem cell transplantation was performed. In minimal residual disease monitoring, FLT3-ITD negativity after consolidation therapy was a valuable predictor of better OS (P<0.001) and EFS (P<0.001). FLT3-ITD poor prognostic group with high mutant allele burden or long ITD length is efficiently identified by quantitative fragment analysis.
doi:10.1038/bcj.2015.61
PMCID: PMC4558586  PMID: 26832846
20.  Activated STING in a Vascular and Pulmonary Syndrome 
The New England journal of medicine  2014;371(6):507-518.
BACKGROUND
The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.
METHODS
We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-β, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls.
RESULTS
We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mono-nuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibro-blasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors.
CONCLUSIONS
STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173.
doi:10.1056/NEJMoa1312625
PMCID: PMC4174543  PMID: 25029335
21.  G0/G1 switch gene 2 has a critical role in adipocyte differentiation 
Cell Death and Differentiation  2014;21(7):1071-1080.
Mouse 3T3-L1 preadipocytes differentiate into adipocytes when treated with 3-isobutyl-1-methylxanthine, dexamethasone, and insulin. Although mechanisms of adipogenesis, including transcriptional cascades, are understood, it is still unclear how clonally expanded cells eventually enter the terminal differentiation program. From gene expression profile studies, we identified G0/G1 switch gene 2 (G0s2) as a novel regulator of adipogenesis. The gene was found to be expressed at a higher level in white and brown adipose tissues, and it was induced in 3T3-L1 cells by hormonal treatment. Importantly, G0s2 expression was closely associated with the transition from mitotic clonal expansion to terminal differentiation. Knockdown of G0s2 expression with siRNA inhibited adipocyte differentiation, whereas constitutive overexpression of G0s2 accelerated differentiation of preadipocytes to mature adipocytes. Expression of G0s2 was found to be regulated by peroxisome proliferator-activated receptor γ (PPARγ), which is a well-known regulator of adipocyte differentiation. Absence of either PPARγ or G0s2 expression resulted in apoptotic pathway activation before terminal differentiation. To determine whether G0s2 has a role in vivo, G0s2-knockout mice were generated. The knockout mice were normal in appearance, but they had less adipose mass than wild-type littermates. Mouse embryonic fibroblast cells from G0s2-deficient mice exhibited impaired adipogenesis and contained unusually small intracellular lipid droplets, suggesting that G0s2 has a role in lipid droplet formation. Our studies demonstrate that G0s2 has an important role in adipogenesis and accumulation of triacylglycerol.
doi:10.1038/cdd.2014.26
PMCID: PMC4207475  PMID: 24583640
22.  NOD2 Mediates Odontoblast Differentiation and RANKL Expression 
Journal of Dental Research  2014;93(7):678-684.
The precise regulation of odontoblast differentiation and osteoclastogenic cytokine expression in human dental pulp cells (HDPCs) is crucial for the pathology of bacteria-related pulpitis. Although the up-regulation of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been reported in inflamed human dental pulps, the role of NOD2 in the differentiation of HDPCs remains unclear. Here, we show the involvement of NOD2 in odontoblast differentiation together with osteoclastogenic cytokine expression in HDPCs. Treatment with muramyl dipeptide (MDP), a known NOD2-agonist, significantly inhibited odontoblast differentiation of HDPCs, as revealed by reduced ALP activity, osteoblast/odontoblast marker expression, and mineralized nodule formation. Importantly, the forced down-regulation of NOD2 by small interfering RNA (siRNA) recovered MDP-down-regulated odontoblast differentiation. MDP-elicited suppression of odontoblast differentiation resulted from the increased expression of MKP-1 protein and the subsequent decline of MAPKs phosphorylation, which is a prerequisite for odontoblast differentiation. Furthermore, we found that MDP treatment elevated the expression of osteoclastogenic cytokines in HDPCs, which was also reversed by NOD2 silencing. Analysis of these data, taken together, suggests that the regulation of NOD2 expression upon MDP challenge might serve as an intrinsic mechanism that underlies the hindered dentin formation and accelerated dentin resorption in bacterial infection-mediated pulpitis.
Abbreviations: HDPCs, human dental pulp cells; NOD2, nucleotide-binding oligomerization domain-containing protein 2; MDP, muramyl dipeptide; siRNA, small interfering RNA; MAPKs, mitogen-activated protein kinases; MKP-1, MAPK phosphatase-1; BMMs, bone-marrow-derived macrophages; and CM, conditioned medium.
doi:10.1177/0022034514535214
PMCID: PMC4293730  PMID: 24820666
pulpitis; dental pulp; muramyl dipeptide; osteoclasts; osteoblasts; Map kinase phosphatase 1
23.  Diffusion-Weighted Imaging of Orbital Masses: Multi-Institutional Data Support a 2-ADC Threshold Model to Categorize Lesions as Benign, Malignant, or Indeterminate 
BACKGROUND AND PURPOSE
DWI has been increasingly used to characterize orbital masses and provides quantitative information in the form of the ADC, but studies of DWI of orbital masses have shown a range of reported sensitivities, specificities, and optimal threshold ADC values for distinguishing benign from malignant lesions. Our goal was to determine the optimal use of DWI for imaging orbital masses through aggregation of data from multiple centers.
MATERIALS AND METHODS
Source data from 3 previous studies of orbital mass DWI were aggregated, and additional published data points were gathered. Receiver operating characteristic analysis was performed to determine the sensitivity, specificity, and optimal ADC thresholds for distinguishing benign from malignant masses.
RESULTS
There was no single ADC threshold that characterized orbital masses as benign or malignant with high sensitivity and specificity. An ADC of less than 0.93 × 10−3 mm2/s was more than 90% specific for malignancy, and an ADC of less than 1.35 × 10−3 mm2/s was more than 90% sensitive for malignancy. With these 2 thresholds, 33% of this cohort could be characterized as “likely malignant,” 29% as “likely benign,” and 38% as “indeterminate.”
CONCLUSIONS
No single ADC threshold is highly sensitive and specific for characterizing orbital masses as benign or malignant. If we used 2 thresholds to divide these lesions into 3 categories, however, a majority of orbital masses can be characterized with >90% confidence.
doi:10.3174/ajnr.A3619
PMCID: PMC4138308  PMID: 23868150
24.  Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia 
Molecular Psychiatry  2014;20(3):361-368.
Consistent with recent reports indicating that neurons differentiated in vitro from human-induced pluripotent stem cells (hiPSCs) are immature relative to those in the human brain, gene expression comparisons of our hiPSC-derived neurons to the Allen BrainSpan Atlas indicate that they most resemble fetal brain tissue. This finding suggests that, rather than modeling the late features of schizophrenia (SZ), hiPSC-based models may be better suited for the study of disease predisposition. We now report that a significant fraction of the gene signature of SZ hiPSC-derived neurons is conserved in SZ hiPSC neural progenitor cells (NPCs). We used two independent discovery-based approaches—microarray gene expression and stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomic mass spectrometry analyses—to identify cellular phenotypes in SZ hiPSC NPCs from four SZ patients. From our findings that SZ hiPSC NPCs show abnormal gene expression and protein levels related to cytoskeletal remodeling and oxidative stress, we predicted, and subsequently observed, aberrant migration and increased oxidative stress in SZ hiPSC NPCs. These reproducible NPC phenotypes were identified through scalable assays that can be applied to expanded cohorts of SZ patients, making them a potentially valuable tool with which to study the developmental mechanisms contributing to SZ.
doi:10.1038/mp.2014.22
PMCID: PMC4182344  PMID: 24686136
25.  Gadoxetic acid-enhanced MRI for T-staging of gallbladder carcinoma: emphasis on liver invasion 
The British Journal of Radiology  2013;87(1033):20130608.
Objective:
To evaluate the diagnostic performance of gadoxetic acid-enhanced MRI with an emphasis on the usefulness of the hepatobiliary phase (HBP) in T-staging of gallbladder carcinoma.
Methods:
66 patients with surgically confirmed gallbladder carcinoma underwent MRI. Two radiologists independently reviewed two sets of gadoxetic acid-enhanced MRI without and with the HBP. Local tumour spread was evaluated according to T-staging, and the results were compared with pathological findings. The diagnostic performance of two image sets to differentiate each T-stage was compared.
Results:
The sensitivities of MRI with the HBP to differentiate T1 vs ≥T2 lesions, ≤T2 vs ≥T3 lesions and ≤T3 vs T4 lesions were 96.3%, 85.7% and 100% for Observer 1 and 92.6%, 95.2% and 100% for Observer 2, respectively (p < 0.0001). By adding the HBP, the sensitivities to differentiate ≤T2 vs ≥T3 lesions were increased from 66.7% to 85.7% for Observer 1 and from 81.0% to 95.2% for Observer 2, although there was no significant difference (p > 0.05). The overall accuracies for T-staging were increased from 80.3% to 86.4% for Observer 1, a statistically significant degree (p = 0.046), and from 83.8% to 87.9% for Observer 2 (p > 0.05). The k-value for the two observers indicated excellent agreement.
Conclusion:
Gadoxetic acid-enhanced MRI provided acceptable diagnostic performance for T-staging of gallbladder carcinoma. Addition of the HBP aids in the detection of liver invasion.
Advances in knowledge:
In the T-staging of gallbladder carcinoma, gadoxetic acid-enhanced MRI with the HBP may enhance detection of liver invasion.
doi:10.1259/bjr.20130608
PMCID: PMC3898979  PMID: 24288397

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