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1.  Characterization of two alkyl hydroperoxide reductase C homologs alkyl hydroperoxide reductase C_H1 and alkyl hydroperoxide reductase C_H2 in Bacillus subtilis 
AIM: To identify alkyl hydroperoxide reductase subunit C (AhpC) homologs in Bacillus subtilis (B. subtilis) and to characterize their structural and biochemical properties. AhpC is responsible for the detoxification of reactive oxygen species in bacteria.
METHODS: Two AhpC homologs (AhpC_H1 and AhpC_H2) were identified by searching the B. subtilis database; these were then cloned and expressed in Escherichia coli. AhpC mutants carrying substitutions of catalytically important Cys residues (C37S, C47S, C166S, C37/47S, C37/166S, C47/166S, and C37/47/166S for AhpC_H1; C52S, C169S, and C52/169S for AhpC_H2) were obtained by site-directed mutagenesis and purified, and their structure-function relationship was analyzed. The B. subtilis ahpC genes were disrupted by the short flanking homology method, and the phenotypes of the resulting AhpC-deficient bacteria were examined.
RESULTS: Comparative characterization of AhpC homologs indicates that AhpC_H1 contains an extra C37, which forms a disulfide bond with the peroxidatic C47, and behaves like an atypical 2-Cys AhpC, while AhpC_H2 functions like a typical 2-Cys AhpC. Tryptic digestion analysis demonstrated the presence of intramolecular Cys37-Cys47 linkage, which could be reduced by thioredoxin, resulting in the association of the dimer into higher-molecular-mass complexes. Peroxidase activity analysis of Cys→Ser mutants indicated that three Cys residues were involved in the catalysis. AhpC_H1 was resistant to inactivation by peroxide substrates, but had lower activity at physiological H2O2 concentrations compared to AhpC_H2, suggesting that in B. subtilis, the enzymes may be physiologically functional at different substrate concentrations. The exposure to organic peroxides induced AhpC_H1 expression, while AhpC_H1-deficient mutants exhibited growth retardation in the stationary phase, suggesting the role of AhpC_H1 as an antioxidant scavenger of lipid hydroperoxides and a stress-response factor in B. subtilis.
CONCLUSION: AhpC_H1, a novel atypical 2-Cys AhpC, is functionally distinct from AhpC_H2, a typical 2-Cys AhpC.
doi:10.4331/wjbc.v6.i3.249
PMCID: PMC4549766  PMID: 26322180
Cysteine-dependent peroxidase; Thioredoxin; Thiol peroxidase; Peroxiredoxin; Alkyl hydroperoxide; Ortholog; Bacillus subtilis; Oxidative stress
2.  In Vitro and In Vivo Radiosensitizing Effect of Valproic Acid on Fractionated Irradiation 
Purpose
This study was conducted in order to validate the radiosensitization effect of valproic acid, a biologically available histone deacetylase inhibitor, for fractionated radiation.
Materials and Methods
Radiosensitization effect of valproic acid was tested for the A549 cell line and U87MG cell line in vitro. Fractionated irradiation of 12 Gy in four fractions was administered on D2-5 with valproic acid, 150 mg/Kg, ip, bid for six consecutive days (D1-6) to A549 and U87MG tumors implanted in BALB/c-nude mice. A growth delay curve was formulated.
Results
Radiosensitization effect of valproic acid was found for both cell lines; A549 at 1.5 mM and 3.0 mM concentration and U87MG at 3.0 mM concentration. In growth delay analysis, a statistically significant radiosensitization effect was observed for both tumors (p < 0.001 for both tumors). Difference for change in slope for control and valproic acid versus radiotherapy and radiotherapy plus valproic acid showed borderline significance for the U87MG cell line (p=0.065), indicating beyond additive effect, whereas this difference was statistically insignificant for A549 tumor (p=0.951), indicating additive effect.
Conclusion
Results of this study indicate that a radiosensitizing effect for fractionated radiotherapy of valproic acid for A549 and U87MG tumors in vivo is evident and that it may be more than additive for U87MG tumors. Further exploitation of histone deacetylase inhibitors in clinical trials is warranted.
doi:10.4143/crt.2014.026
PMCID: PMC4506108  PMID: 25600060
Radiation tolerance; Valproic acid; Radiation; Glioblastoma; Non-small-cell lung carcinoma
3.  Low-Dose Whole Brain Radiotherapy with Tumor Bed Boost after Methotrexate-Based Chemotherapy for Primary Central Nervous System Lymphoma 
Purpose
The purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL).
Materials and Methods
We retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The median dose to the whole brain and to the tumor bed was 27 Gy (range, 18 to 36 Gy) and 50.4 Gy (range, 45 to 54 Gy), respectively.
Results
With a median follow-up period of 27 months, 55 patients (85.9%) achieved complete response (CR). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 52.6% and 39.3%, respectively. In univariate analysis, factors associated with OS were age, performance status, involvement of deep structure, and CR to sequential chemoradiotherapy (CRT). These variables remained as significant factors for OS in multivariate analysis. CR to sequential CRT was the only positive factor associated with PFS (p=0.009). Neurologic toxicity was more common in elderly patients older than 60 years (p=0.025).
Conclusion
Low-dose WBRT with tumor bed boost after methotrexate-based chemotherapy might be an effective method for management of PCNSL.
doi:10.4143/crt.2014.46.3.261
PMCID: PMC4132445  PMID: 25038761
Radiotherapy; Methotrexate; Central nervous system; Lymphoma
4.  Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041 
Purpose
This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation.
Materials and Methods
The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution.
Results
TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naïve cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest.
Conclusion
TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained.
doi:10.4143/crt.2013.45.4.334
PMCID: PMC3893331  PMID: 24454006
Histone deacetylase inhibitors; Radiation-sensitizing agents; Preclinical drug evaluation
5.  Role of radiotherapy in local control of non-AIDS associated Kaposi's sarcoma patients in Korea: a single institution experience 
Radiation Oncology Journal  2012;30(4):153-157.
Purpose
There has been no definite consensus on standard treatment, either local or systemic, for the Kaposi's sarcoma (KS). Radiotherapy (RT) can be a good local therapeutic choice especially in non-AIDS associated KS (NAKS) for its indolent behavior.
Materials and Methods
Medical records of 17 KS patients treated with RT at the Seoul National University Hospital from February 1998 to January 2012 were retrospectively reviewed. One human immunodeficiency virus (HIV)+ patient with 3 lesions was excluded. The total number of the lesion was 23 among the 16 patients. The median follow-up period was 27.9 months. Correlation between response and variables was analyzed using the logistic regression model. Median age of the patients was 75 years. All the 23 lesions were located at the extremities. Fourteen (61%) of those had pain or local swelling as the initial presentation. Ten patients had possible causes of immunodeficiency and were regarded as iatrogenic, and other 6 were classic KS. Median dose of RT was 36 Gy.
Results
No KS-related death was observed. Excluding 2 with short-term follow-up only, complete response and partial response were obtained in 2 (9%) and 19 (73%) lesions, respectively. Of those, 3 lesions underwent local progression. Six had out-of-field recurrence after RT. Symptom improvement was achieved in 13 (93%) of 14 patients. Grade 2 skin toxicities were found in 9 lesions but all got improvement after treatment. When divided into responsive and progressive group, free from progression was not related to any of the possible variables.
Conclusion
RT is effective in local control of NAKS resulting great response rate.
doi:10.3857/roj.2012.30.4.153
PMCID: PMC3546282  PMID: 23346533
Kaposi sarcoma; Radiotherapy; Local control
6.  BI-17EARLY COGNITIVE FUNCTION TESTS PREDICT EARLY PROGRESSION IN NEWLY-DIAGNOSED GLIOBLASTOMA 
Neuro-Oncology  2014;16(Suppl 5):v26-v27.
BACKGROUND: Cognitive dysfunction is a characteristic of tumor infiltration and a major morbidity causing functional deterioration in glioblastoma patients. Here we investigated whether pre-operative cognitive function tests can predict early prognosis in glioblastoma. METHODS: Consecutive patients who underwent glioma surgery were evaluated with pre-operative cognitive function tests, including Mini-Mental State Examination, Geriatric Depression Scale, Digit Span Tests (forward and backward), Controlled Oral Ward Association Test, Trail-Making Tests (TMT, type a, b, and c), and Stroop Tests. Pathologically-confirmed glioblastoma were treated with the standard protocol using radiation and temozolomide, and the 6-month progression-free survivals (PFS-6) were analyzed. RESULTS: Among 126 patients who underwent glioma surgery, 55 patients were diagnosed as glioblastoma, and 50 patients were finally eligible for the PFS-6 analysis. Thirty four patients (68%) achieved PFS-6. In the comparison of those without progression (PFS-6) with those with progression (No-PFS-6), there was no difference in the patients' demographics, tumor locations, tumor sizes, performance scores, initial symptoms, and genetic characteristics of tumors. The PFS-6 patients had higher rates of gross total resection, more use of concomitant chemo-radiation, and longer years of total education, than the no-PFS-6 patients. In the cognitive function tests, the PFS-6 patients had better performance in TMT-a, and TMT-b. Other cognitive function tests were not associated with PFS-6. In multivariate logistic regression, TMT-b was the only independent predictor for PFS-6, while age (<50), total education year (>12 yr), gross total resection, concomitant chemo-radiation, and TMT-a were not. Patients with good performance in TMT-b not only showed better early prognosis in the Kaplan-Meier survival analysis, but also had better recursive partitioning analysis classes. CONCLUSION: Our results indicate that the early cognitive function test before surgery can predict the early prognosis in glioblastoma. Poor executive function and slow psychomotor speed as detected in TMT suggest early progression of the tumor.
doi:10.1093/neuonc/nou239.17
PMCID: PMC4217884
7.  Prediction of Response to Concurrent Chemoradiotherapy with Temozolomide in Glioblastoma: Application of Immediate Post-Operative Dynamic Susceptibility Contrast and Diffusion-Weighted MR Imaging 
Korean Journal of Radiology  2015;16(6):1341-1348.
Objective
To determine whether histogram values of the normalized apparent diffusion coefficient (nADC) and normalized cerebral blood volume (nCBV) maps obtained in contrast-enhancing lesions detected on immediate post-operative MR imaging can be used to predict the patient response to concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ).
Materials and Methods
Twenty-four patients with GBM who had shown measurable contrast enhancement on immediate post-operative MR imaging and had subsequently undergone CCRT with TMZ were retrospectively analyzed. The corresponding histogram parameters of nCBV and nADC maps for measurable contrast-enhancing lesions were calculated. Patient groups with progression (n = 11) and non-progression (n = 13) at one year after the operation were identified, and the histogram parameters were compared between the two groups. Receiver operating characteristic (ROC) analysis was used to determine the best cutoff value for predicting progression. Progression-free survival (PFS) was determined with the Kaplan-Meier method and the log-rank test.
Results
The 99th percentile of the cumulative nCBV histogram (nCBV C99) on immediate post-operative MR imaging was a significant predictor of one-year progression (p = 0.033). ROC analysis showed that the best cutoff value for predicting progression after CCRT was 5.537 (sensitivity and specificity were 72.7% and 76.9%, respectively). The patients with an nCBV C99 of < 5.537 had a significantly longer PFS than those with an nCBV C99 of ≥ 5.537 (p = 0.026).
Conclusion
The nCBV C99 from the cumulative histogram analysis of the nCBV from immediate post-operative MR imaging may be feasible for predicting glioblastoma response to CCRT with TMZ.
doi:10.3348/kjr.2015.16.6.1341
PMCID: PMC4644757  PMID: 26576125
Glioblastoma; Temozolomide; Apparent diffusion coefficient; Cerebral blood volume; Histogram analysis
8.  Nonrigid Registration of 2-D and 3-D Dynamic Cell Nuclei Images for Improved Classification of Subcellular Particle Motion 
The observed motion of subcellular particles in fluorescence microscopy image sequences of live cells is generally a superposition of the motion and deformation of the cell and the motion of the particles. Decoupling the two types of movements to enable accurate classification of the particle motion requires the application of registration algorithms. We have developed an intensity-based approach for nonrigid registration of multi-channel microscopy image sequences of cell nuclei. First, based on 3-D synthetic images we demonstrate that cell nucleus deformations change the observed motion types of particles and that our approach allows to recover the original motion. Second, we have successfully applied our approach to register 2-D and 3-D real microscopy image sequences. A quantitative experimental comparison with previous approaches for nonrigid registration of cell microscopy has also been performed.
doi:10.1109/TIP.2010.2076377
PMCID: PMC3282047  PMID: 20840894
Biomedical image processing; image sequence analysis; microscopy; registration
9.  Extra-cranial Malignant Rhabdoid Tumor in Children: A Single Institute Experience 
Purpose
Malignant rhabdoid tumor (MRT) is a rare and highly aggressive tumor that affects young children. Due to its extreme rarity, most of the available data are based on retrospective case series. To add to the current knowledge of this disease, we reviewed the patients treated for extra-cranial MRT in our institute.
Materials and Methods
A retrospective medical record review was conducted on children treated for pathologically confirmed extra-cranial MRT at Seoul National University Children’s Hospital between January 2003 and May 2013.
Results
Eleven patients (7 boys, 4 girls) were diagnosed with extra-cranial MRT at a median age of 9 months old. INI1 staining was important in the pathological confirmation. Six patients (55%) had renal MRT and five (45%) had soft tissue MRT. Five patients (45%) had metastases at diagnosis. All patients underwent chemotherapy, eight patients (73%) underwent surgery, six patients (55%) received therapeutic radiotherapy, and four patients (36%) underwent high dose chemotherapy with autologous stem cell rescue (HDCT/ASCR) with melphalan, etoposide, and carboplatin. Five patients (45%) died of disease following progression (n=3) or relapse (n=2), however, there was no treatment related mortality. The overall survival of the cohort was 53.0% and the event-free survival was 54.5% with a median follow-up duration of 17.8 months (range, 2.3 to 112.3 months).
Conclusion
Extra-cranial MRT is still a highly aggressive tumor in young children. However, the improved survival of our cohort is promising and HDCT/ASCR with melphalan, etoposide, and carboplatin may be a promising treatment option.
doi:10.4143/crt.2013.176
PMCID: PMC4614222  PMID: 25672587
Rhabdoid tumor; Kidney neoplasms; Soft tissue neoplasms; Neoplasm metastasis
10.  MR Imaging Evaluation of Intracerebral Hemorrhages and T2 Hyperintense White Matter Lesions Appearing after Radiation Therapy in Adult Patients with Primary Brain Tumors 
PLoS ONE  2015;10(8):e0136795.
The purpose of our study was to determine the frequency and severity of intracerebral hemorrhages and T2 hyperintense white matter lesions (WMLs) following radiation therapy for brain tumors in adult patients. Of 648 adult brain tumor patients who received radiation therapy at our institute, magnetic resonance (MR) image data consisting of a gradient echo (GRE) and FLAIR T2-weighted image were available three and five years after radiation therapy in 81 patients. Intracerebral hemorrhage was defined as a hypointense dot lesion appearing on GRE images after radiation therapy. The number and size of the lesions were evaluated. The T2 hyperintense WMLs observed on the FLAIR sequences were graded according to the extent of the lesion. Intracerebral hemorrhage was detected in 21 (25.9%) and 35 (43.2) patients in the three- and five-year follow-up images, respectively. The number of intracerebral hemorrhages per patient tended to increase as the follow-up period increased, whereas the size of the intracerebral hemorrhages exhibited little variation over the course of follow-up. T2 hyperintense WMLs were observed in 27 (33.3%) and 32 (39.5) patients in the three and five year follow-up images, respectively. The age at the time of radiation therapy was significantly higher (p < 0.001) in the patients with T2 hyperintense WMLs than in those without lesions. Intracerebral hemorrhages are not uncommon in adult brain tumor patients undergoing radiation therapy. The incidence and number of intracerebral hemorrhages increased over the course of follow-up. T2 hyperintense WMLs were observed in more than one-third of the study population.
doi:10.1371/journal.pone.0136795
PMCID: PMC4556481  PMID: 26322780
11.  In vivo imaging of activated microglia in a mouse model of focal cerebral ischemia by two-photon microscopy 
Biomedical Optics Express  2015;6(9):3303-3312.
Microglia are brain resident macrophages rapidly responding to various stimuli to exert appropriate inflammatory responses. Although they have recently been exploited as an attractive candidate for imaging neuroinflammation, it is still difficult to visualize them at the cellular and molecular levels. Here we imaged activated microglia by establishing intracranial window chamber (ICW) in a mouse model of focal cerebral ischemia by using two-photon microscopy (TPM), in vivo. Intravenous injection of fluorescent antibodies allowed us to detect significantly elevated levels of Iba-1 and CD68 positive activated microglia in the ipsilateral compared to the contralateral side of the infarct. We further observed that indomethacin, a non-steroidal anti-inflammatory drug significantly attenuated CD68-positive microglial activation in ICW, which was further confirmed by qRT-PCR biochemical analyses. In conclusion, we believe that in vivo TPM imaging of ICW would be a useful tool to screen for therapeutic interventions lowering microglial activation hence neuroinflammation.
doi:10.1364/BOE.6.003303
PMCID: PMC4574658  PMID: 26417502
(000.1430) Biology and medicine; (180.2520) Fluorescence microscopy; (180.4315) Nonlinear microscopy
12.  Evaluation of variability in target volume delineation for newly diagnosed glioblastoma: a multi-institutional study from the Korean Radiation Oncology Group 
Background
This study aimed for a collaborative evaluation of variability in the target volumes for glioblastoma, determined and contoured by different radiotherapy (RT) facilities in Korea.
Methods
Fifteen panels of radiation oncologists from independent institutions contoured the gross target volumes (GTVs) and clinical target volumes (CTVs) for 3-dimensional conformal RT or intensity-modulated RT on each simulation CT images, after scrutinizing the enhanced T1-weighted and T2-weighted-fluid-attenuated inversion recovery MR images of 9 different cases of glioblastoma. Degrees of contouring agreement were analyzed by the kappa statistics. Using the algorithm of simultaneous truth and performance level estimation (STAPLE), GTVSTAPLE and CTVSTAPLE contours were derived.
Results
Contour agreement was moderate (mean kappa 0.58) among the GTVs and was substantial (mean kappa 0.65) among the CTVs. However, each panels’ GTVs and modification of CTVs regarding anatomical structures varied. Three-fourth of contoured panels’ CTVs encompassed the peritumoral areas of T2-high signal intensity (T2-HSI). Nine of nine GTVSTAPLE encompased the surgical cavity and the T1-enhanced lesions. Eight of nine CTVSTAPLE encompassed the peritumoral T2-HSI area. The median MARGIN90 and the median MARGIN95 were 1.4 cm and 1.5 cm, respectively.
Conclusions
Moderate to substantial agreement existed in target volumes for 3-dimensional or intensity-modulated RT determined by radiation oncologists in Korea. According to the estimated consensus contours, the initial CTV encompassed the GTV with margin less than 2.0 cm and the whole peritumoral areas of T2-HSI. The findings of our study propose the need for further studies and modified guidelines.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-015-0439-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13014-015-0439-z
PMCID: PMC4489390  PMID: 26134973
Glioblastoma; Target volume; Peritumoral edema; STAPLE; Margin
13.  The Role of Radiotherapy in the Treatment of Newly Diagnosed Supratentorial Low-grade Oligodendrogliomas: Comparative Analysis with Immediate Radiotherapy versus Surgery Alone 
Purpose
The purpose of this study was to evaluate the role of immediate postoperative radiotherapy (RT) in adult patients with a low-grade oligodendroglioma (LODG).
Materials and Methods
A total of 74 patients, older than 15 years, were treated in our institution between April 1990 and March 2006 for newly diagnosed LODGs. After surgery, 43 patients were treated with immediate RT with a total dose of 54~55.8 Gy with 1.8 Gy fractions (RT group) and 31 patients were followed with no adjuvant RT (OP group). All patients were closely observed until tumor progression or death with frequent work-ups including neurological examinations and MRI. Primary endpoints were overall survival and progression-free survival. The median follow-up duration of survivors was 6.2 years in the RT group and 5.8 years in the OP group.
Results
Median progression-free survival was 13.2 years in the RT group and 4.6 years in the OP group; multivariate analysis confirmed improved outcome with the use of immediate RT (hazard ratio, 0.22; 95% confidence interval-CI, 0.09~0.55; p<0.001). Median overall survival was 14.9 years in the RT group and 9.8 years in the OP group; the use of adjuvant RT was also associated with a trend toward better overall survival after immediate RT based on multivariate analysis (hazard ratio, 0.3; 95% CI, 0.08~1.17; p=0.082). No severe RT related complications were observed.
Conclusion
Immediate RT following surgery appears to be an effective treatment modality for supratentorial LODGs. However, the potential benefit of adjuvant RT for overall survival needs to be tested prospectively in the future.
doi:10.4143/crt.2009.41.3.132
PMCID: PMC2757663  PMID: 19809562
Brain neoplasms; Oligodendroglioma; Radiotherapy
14.  Texture analysis on the edge-enhanced fluence of VMAT 
Background
Textural features of edge-enhanced fluence were analysed to quantify modulation degree of volumetric modulated arc therapy (VMAT) plans.
Methods
Twenty prostate and twenty head and neck VMAT plans were retrospectively selected. Fluences of VMAT plans were generated by integration of monitor units shaped by multi-leaf collimators (MLCs) at each control point. When generating fluences, the values of pixels representing MLC tips were doubled to prevent smearing out of small or irregular fields (edge-enhancement). Six kinds of textural features, including angular second moment, inverse difference moment, contrast, variance, correlation and entropy, were calculated with particular displacement distances (d) of 1, 5 and 10. Plan delivery accuracy was evaluated by gamma-index method, mechanical parameter differences between plan and delivery and differences in dose-volumetric parameters between plan and delivery. Spearman’s correlation coefficients (rs) were calculated between the values of textural features and VMAT delivery accuracy.
Results
The rs values of contrast (d = 1) with edge-enhancement to global gamma passing rates with 2%/2 mm, 1%/2 mm and 2%/1 mm were 0.546 (p < 0.001), 0.744 (p < 0.001) and 0.487 (p = 0.001), respectively. Those with local 2%/2 mm, 1%/2 mm and 2%/1 mm were 0.588, 0.640 and 0.644, respectively (all with p < 0.001). The rs values of contrast (d = 1) to MLC and gantry angle errors were -0.853 and 0.655, respectively (all with p < 0.001). The contrast (d = 1) showed statistically significant rs values in 11 dose-volumetric parameter differences from a total of 35 cases, and generally showed better correlations to plan delivery accuracy than did previously suggested textural features with non-edge-enhanced fluences, as well as conventional modulation indices.
Conclusions
Contrast (d = 1) with edge-enhanced fluences could be used as modulation index for VMAT.
doi:10.1186/s13014-015-0382-z
PMCID: PMC4386104  PMID: 25890104
Texture analysis; Volumetric modulated arc therapy; Modulation index; Fluence
15.  A Histone Deacetylase Inhibitor, Trichostatin A, Enhances Radiosensitivity by Abrogating G2/M Arrest in Human Carcinoma Cells 
Purpose
Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components in anticancer therapy. In this study, we tried to confirm the radiosensitizing effect of trichostatin A (TSA) on a panel of human carcinoma cell lines and elucidate its mechanism of interaction.
Materials and Methods
A549, HeLa and Caski cells were exposed to TSA for 18 hr prior to irradiation, and the cell survival then measured using a clonogenic assay. Western blot and flow cytometric analyses, for histone acetylation, and cell cycle and apoptosis, respectively, were also performed.
Results
TSA increased the acetylation of histone H3. The pretreatment of TSA consistently radiosensitized all three cell lines. The SF2 (surviving fraction at 2 Gy) of TSA-treated cells was significantly lower than that of mock treated cells. The SER (sensitizer enhancement ratio) increased in all 3 cell lines, in concentration dependent manners. The TSA treated cells showed abrogation of radiation-induced G2/M arrest, in a concentration dependent manner.
Conclusion
The pretreatment of TSA enhanced the radiosensitivity of a panel of human carcinoma cells, which was attributed, in part, to the abrogation of radiation-induced G2/M arrest.
doi:10.4143/crt.2005.37.2.122
PMCID: PMC2785402  PMID: 19956491
Trichostatin A; Histone deacetylase inhibitor; Radiosensitization; G2/M arrest
16.  Outcome and Prognostic Factors of Childhood Diffuse Brainstem Glioma 
Purpose
The outcome and prognostic factors of brainstem glioma were evaluated following radiotherapy methods.
Materials and Methods
Between 1986 and 2001, 45 childhood patients with diffuse brainstem glioma were treated. There were 26 boys and 19 girls, with a median age of 7 years (range 3~18). The histopathological diagnoses were confirmed in 13 patients, which revealed a low-grade glioma in four patients, and high-grade glioma in the other nine. Before 1993, radiation therapy using a regime of 1.8 to 2.0 Gy once a day was performed in 16 cases; thereafter, a regimes of 1.1 or 1.5 Gy twice a day was given in 15 and 14 cases, respectively. Nine patients were treated with adjuvant chemotherapy. The response to the treatment was evaluated by the MRI findings 4 weeks after radiotherapy.
Results
After radiotherapy, the neurological deficit improved in 42 of the 45 patients (93%). The MRI responses were as follows; partial response 22/39 (56%), minimal to no response in 16/39 (41%) and tumor progression in 1/39 (3%). The median time to disease progression was 7 months, and the median survival was 12 months; the overall survival rate at 1 year was 41%. There was no significant prognostic factor for overall survival. The progression-free survival was influenced by the tumor histology (low grade vs. high grade, p=0.05) in those patients whose pathology was confirmed.
Conclusion
The radiation therapy fractionation schedule did not influence the survival. Low grade histology was a possible favorable prognostic factor of progression-free survival in pediatric brainstem glioma patients.
doi:10.4143/crt.2005.37.2.109
PMCID: PMC2785398  PMID: 19956489
Brainstem glioma; Radiotherapy
17.  Prognosis Prediction of Measurable Enhancing Lesion after Completion of Standard Concomitant Chemoradiotherapy and Adjuvant Temozolomide in Glioblastoma Patients: Application of Dynamic Susceptibility Contrast Perfusion and Diffusion-Weighted Imaging 
PLoS ONE  2014;9(11):e113587.
Purpose
To assess the prognosis predictability of a measurable enhancing lesion using histogram parameters produced by the normalized cerebral blood volume (nCBV) and normalized apparent diffusion coefficient (nADC) after completion of standard concomitant chemoradiotherapy (CCRT) and adjuvant temozolomide (TMZ) medication in glioblastoma multiforme (GBM) patients.
Materials and Methods
This study was approved by the institutional review board (IRB), and the requirement for informed consent was waived. A total of 59 patients with newly diagnosed GBM who received standard CCRT with TMZ and adjuvant TMZ for six cycles underwent perfusion-weighted and diffusion-weighted imaging. Twenty-seven patients had a measurable enhancing lesion and 32 patients lacked a measurable enhancing lesion based on the Response Assessment in Neuro-Oncology (RANO) criteria in the follow-up MRI, which was performed within 3 months after adjuvant TMZ therapy was completed. We measured the nCBV and nADC histogram parameters based on the measurable enhancing lesion. The progression free survival (PFS) was analyzed by the Kaplan-Meier method with the use of the log-rank test.
Results
The median PFS of patients lacking measurable enhancing lesion was longer than for those with measurable enhancing lesions (17.6 vs 3.3 months, P<.0001). There was a significant, positive correlation between the 99th percentile nCBV value of a measurable enhancing lesion and the PFS (P = .044, R2 = .152). In addition, the median PFS was longer in patients with a 99th percentile nCBV value ≧4.5 than it was in those with a value <4.5 (4.4 vs 3.1 months, P = .036).
Conclusion
We found that the nCBV value can be used for the prognosis prediction of a measurable enhancing lesion after the completion of standard treatment for GBM, wherein a high 99th percentile nCBV value (≧4.5) suggests a better PFS for GBM patients.
doi:10.1371/journal.pone.0113587
PMCID: PMC4242641  PMID: 25419975
18.  Dosimetric comparison of 4 MeV and 6 MeV electron beams for total skin irradiation 
Background
In this study, dosimetric aspects of TSEI consisting of a 4 MeV beam with no spoiler were investigated in comparison to a nominal 6 MeV beam with spoiler, and the potential for clinical applications was evaluated.
Methods
The TSEI technique is based on the Stanford technique, which utilizes a beam configuration of six-dual fields. MOSFETs were used to measure the optimal gantry angle, profile uniformity, and absolute dose at the calibration point. The depth dose curve of the central axis was measured in the treatment plane using EBT2 film. Photon contamination was measured as the dose at 5 cm depth in a solid water phantom relative to the maximum dose using a parallel plate ion chamber. A MOSFET dosimeter placed on the surface of a humanoid phantom, and EBT2 films inserted into a humanoid phantom were used to verify the TSEI commissioning.
Results
Dosimetric aspects of the 4 MeV TSEI beam, such as profile uniformity (±10%) and relative photon contamination (<0.001%), were comparable to those of a 6 MeV TSEI beam. The relative depth dose of the 4 MeV electrons was 81.4% at the surface and 100% at 0.4 cm. For the 6 MeV electrons, the relative depth dose was 93.4% at the surface and 100% from 0.2 cm to 0.4 cm. The calculated B-factor of the 4 MeV TSEI beam was 1.55, and 1.53 for the 6 MeV TSEI. 80% of the prescribed dose was obtained at 0.22 cm depth for the 4 MeV TSEI beam and 0.53 cm for the 6 MeV TSEI beam in the humanoid phantom measurement.
Conclusions
The suggested 4 MeV beam for TSEI could be applied to shallow depth skin diseases and to electron boost as second treatment course.
doi:10.1186/1748-717X-9-197
PMCID: PMC4261910  PMID: 25194217
Total skin electron irradiation (TSEI); Electron energy; Stanford Technique; Mycosis fungoides
19.  A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma 
Neuro-Oncology  2013;15(8):1096-1101.
Background
To determine the benefit of surgical management in recurrent glioblastoma, we analyzed a series of patients with recurrent glioblastoma who had undergone surgery, and we devised a new scale to predict their survival.
Methods
Clinical data from 55 consecutive patients with recurrent glioblastoma were evaluated after surgical management. Kaplan–Meier survival analysis and Cox proportional hazards regression modeling were used to identify prognostic variables for the development of a predictive scale. After the multivariate analysis, performance status (P = .078) and ependymal involvement (P = .025) were selected for inclusion in the new prognostic scale. The devised scale was validated with a separate set of 96 patients from 3 different institutes.
Results
A 3-tier scale (scoring range, 0–2 points) composed of additive scores for the Karnofsky performance status (KPS) (0 for KPS ≥ 70 and 1 for KPS < 70) and ependymal involvement (0 for no enhancement and 1 for enhancement of the ventricle wall in the magnetic resonance imaging) significantly distinguished groups with good (0 points; median survival, 18.0 months), intermediate (1 point; median survival, 10.0 months), and poor prognoses (2 points; median survival, 4.0 months). The new scale was successfully applied to the validation cohort of patients showing distinct prognosis among the groups (median survivals of 11.0, 9.0, and 4.0 months for the 0-, 1-, and 2-point groups, respectively).
Conclusions
We developed a practical scale to facilitate deciding whether to proceed with surgical management in patients with recurrent glioblastoma. This scale was useful for the diagnosis of prognostic groups and can be used to develop guidelines for patient treatment.
doi:10.1093/neuonc/not069
PMCID: PMC3714158  PMID: 23800677
ependymal involvement; performance status; recurrent glioblastoma; scoring system; surgery
20.  Impact of Multimodality Approach for Patients with Leptomeningeal Metastases from Solid Tumors 
Journal of Korean Medical Science  2014;29(8):1094-1101.
The purpose of this study was to evaluate treatment patterns, outcome and prognosticators for patients with leptomeningeal metastases from solid tumor. Medical records of 80 patients from January 1, 2004 to May 31, 2011 were retrospectively reviewed. Most frequent site of origin was the lung (59%) followed by the breast (25%). Most patients were treated with intrathecal chemotherapy (90%) and/or whole brain radiotherapy (67.5%). Systemic therapy was offered to 27 patients (33.8%). Percentage of patients treated with single, dual, and triple modality were 32.5%, 43.8%, and 23.8%, respectively. Median survival was 2.7 months and 1 yr survival rate was 11.3%. Multivariate analysis showed that negative cerebrospinal fluid cytology, fewer chemotherapy regimen prior to leptomeningeal metastases, whole brain radiotherapy, systemic therapy, and combined modality treatment (median survival; single 1.4 vs. dual 2.8 vs. triple 8.3 months, P<0.001) had statistical significance on survival. Subgroup analysis of non-small cell lung cancer (NSCLC) patients showed that targeted therapy had significant independent impact on survival (median survival; 10.5 vs. 3.0 months, P=0.008). Unlike previous reports, survival of patients with NSCLC primary was comparable to breast primary. Furthermore, combined modality treatment for all patients and additionally targeted therapy for NSCLC patients should be considered in the treatment of leptomeningeal metastases from solid tumor.
Graphical Abstract
doi:10.3346/jkms.2014.29.8.1094
PMCID: PMC4129201  PMID: 25120319
Leptomeningeal Metastases; Prognostic Factor; Solid Tumor
21.  Adjuvant single-fraction radiotherapy is safe and effective for intractable keloids 
Journal of Radiation Research  2014;55(5):912-916.
The aim of this study was to assess the feasibility and efficacy of high-dose, single-fraction electron beam radiotherapy for therapy-resistant keloids. Before 2010, intractable keloids were treated at our institution with post-operative irradiation of 6–15 Gy in 3–5 fractionations. For convenience and cost effectiveness, we have changed our treatment protocol to high-dose single-fraction radiotherapy. A total of 12 patients with 16 keloid lesions were treated from January 2010 to January 2013 in our department. A 10-Gy dose of electron irradiation was given within 72 h of the surgical excision. The mean follow-up period was 20 months. Treatments were well tolerated, and there was no recurrence in any of the patients. Severe adverse effects were not observed. Surgical excision of the keloid, followed by immediate, single-fraction, high-dose radiotherapy, is both safe and effective in preventing recurrence of therapy-resistant keloids.
doi:10.1093/jrr/rru025
PMCID: PMC4202283  PMID: 24801475
keloid; radiation; electron beam; single fraction
22.  Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma 
Oncotarget  2014;5(10):3399-3407.
We investigated the role of somatic mutations and a common single nucleotide polymorphism (SNP) in the hTERT promoter region on hTERT expression and clinical outcomes. The hTERT promoter region was sequenced from 48 glioblastomas. hTERT expression was analyzed by quantitative real time-PCR. The association between hTERT promoter genetic changes and other genomic events and clinical variables common in gliomas were examined. C228T and C250T somatic mutations were found in 60.4% of glioblastomas, and a common SNP (T349C) was found in 66.6%. Somatic mutations and the SNP likely have opposing effects on hTERT expression. hTERT expression was significantly higher in the C228T or C250T mutated tumors. Tumors with the T349C genotype showed lower hTERT expression when C228T or C250T mutations were present. However, no significant survival differences were observed among the groups with or without hTERT promoter mutations and SNP. There was a significant association between genetic changes in the hTERT promoter and patient age as well as MGMT promoter methylation and EGFR amplification. hTERT expression is modulated by somatic mutations in the hTERT promoter as well as a common polymorphism. However, hTERT related genomic changes have limited value as an independent prognostic factor for clinical outcomes in glioblastomas.
PMCID: PMC4102818  PMID: 24930669
Glioblastoma; hTERT; promoter mutation; hTERT expression; single nucleotide polymorphism; rs2853669
23.  Thioredoxin 1 as a serum marker for breast cancer and its use in combination with CEA or CA15-3 for improving the sensitivity of breast cancer diagnoses 
BMC Research Notes  2014;7:7.
Background
The human cytosolic thioredoxin (Trx) contains a redox-active dithiol moiety in its conserved active-site sequence. Activation by a wide variety of stimuli leads to secretion of this cytoplasmic protein. Function of Trx1 has been implicated in regulating cell proliferation, differentiation, and apoptosis. The aim of this study was to assess the clinical significance of serum Trx1 level in patients with breast carcinoma.
Results
To clarify whether serum levels of Trx1 could be a serum marker for breast carcinoma, we measured the serum levels of Trx1 in patients with various carcinomas (breast, lung, colorectal, and kidney cancers) using an ELISA, and investigated its associations with the tumour grading from I to III. At the cut-off point 33.1725 ng/ml on the receiver operating characteristic curve (ROC) Trx1 could well discriminate breast carcinoma from normal controls with a sensitivity of 89.8%, specificity 78.0%, and area under the ROC (AUC) 0.901 ± 0.0252. The serum level was well correlated with the progress of the breast carcinoma. We also investigated the diagnostic capacity of CEA and CA15-3 for the early detection of metastatic breast cancer comparing that of Trx1. In contrast to the serum CEA and CA15-3 tumour markers, the serum Trx1 levels of the early cancer (grade I) patients were significantly higher than those of normal control subjects, showing a high diagnostic sensitivity and selectivity (89.4% sensitivity, and 72.0% specificity). The serum levels of Trx1 in various patients with lung, colorectal, and kidney carcinomas indicate that the level of Trx1 is significantly higher than those of other cancer patients. Combinational analysis of CEA or CA15-3 with Trx1 for the detection of breast cancer suggest that the diagnostic capacity of CEA or CA15-3 alone for the early detection of breast cancer, especially regarding sensitivity, is significantly improved by its combination with Trx1.
Conclusions
Taken together, we conclude that serum Trx1 is useful for the early diagnosis of breast cancer or the early prediction prognosis of breast cancer, and therefore has a valuable use as a diagnostic marker and companion marker to CEA and CA15-3 for breast cancer.
doi:10.1186/1756-0500-7-7
PMCID: PMC3891982  PMID: 24393391
Breast cancer; Diagnosis; Thioredoxin 1; Companion marker; Carcinoembryonic antigen (CEA); Cancer antigen 15–3 (CA15-3); Reactive oxygen species
25.  True Progression versus Pseudoprogression in the Treatment of Glioblastomas: A Comparison Study of Normalized Cerebral Blood Volume and Apparent Diffusion Coefficient by Histogram Analysis 
Korean Journal of Radiology  2013;14(4):662-672.
Objective
The purpose of this study was to differentiate true progression from pseudoprogression of glioblastomas treated with concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ) by using histogram analysis of apparent diffusion coefficient (ADC) and normalized cerebral blood volume (nCBV) maps.
Materials and Methods
Twenty patients with histopathologically proven glioblastoma who had received CCRT with TMZ underwent perfusion-weighted imaging and diffusion-weighted imaging (b = 0, 1000 sec/mm2). The corresponding nCBV and ADC maps for the newly visible, entirely enhancing lesions were calculated after the completion of CCRT with TMZ. Two observers independently measured the histogram parameters of the nCBV and ADC maps. The histogram parameters between the true progression group (n = 10) and the pseudoprogression group (n = 10) were compared by use of an unpaired Student's t test and subsequent multivariable stepwise logistic regression analysis to determine the best predictors for the differential diagnosis between the two groups. Receiver operating characteristic analysis was employed to determine the best cutoff values for the histogram parameters that proved to be significant predictors for differentiating true progression from pseudoprogression. Intraclass correlation coefficient was used to determine the level of inter-observer reliability for the histogram parameters.
Results
The 5th percentile value (C5) of the cumulative ADC histograms was a significant predictor for the differential diagnosis between true progression and pseudoprogression (p = 0.044 for observer 1; p = 0.011 for observer 2). Optimal cutoff values of 892 × 10-6 mm2/sec for observer 1 and 907 × 10-6 mm2/sec for observer 2 could help differentiate between the two groups with a sensitivity of 90% and 80%, respectively, a specificity of 90% and 80%, respectively, and an area under the curve of 0.880 and 0.840, respectively. There was no other significant differentiating parameter on the nCBV histograms. Inter-observer reliability was excellent or good for all histogram parameters (intraclass correlation coefficient range: 0.70-0.99).
Conclusion
The C5 of the cumulative ADC histogram can be a promising parameter for the differentiation of true progression from pseudoprogression of newly visible, entirely enhancing lesions after CCRT with TMZ for glioblastomas.
doi:10.3348/kjr.2013.14.4.662
PMCID: PMC3725362  PMID: 23901325
Apparent diffusion coefficient; Cerebral blood volume; Glioblastoma multiforme; Histogram analysis; Pseudoprogression

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