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1.  Lesional location of lateral medullary infarction presenting hiccups (singultus) 
Park, M | Kim, B | Koh, S | Park, M | Park, K | Lee, D
Background: Hiccups are an infrequent result of lateral medullary infarction. Their importance may be underestimated and they can cause distress, exhaustion, and aspiration. Hiccups in lateral medullary infarction remain poorly understood
Objective: To evaluate the relation between the lesional loci of lateral medullary infarction and hiccups.
Methods: 51 patients with lateral medullary infarction were investigated by magnetic resonance imaging within three days of the onset of infarction. Seven of the 51 patients developed hiccup.
Results: All patients with hiccups had middle level lateral medullary lesions, including two with lower level lesions and four with upper level lesions. In the middle level lateral medullary lesions, dorsolateral lesions were most often involved. All patients with lateral medullary infarction presenting with hiccups also had vertigo, dizziness, nausea, vomiting, and dysphagia.
Conclusions: The observations suggest that middle level and dorsolateral lesion locations in lateral medullary infarction frequently induce hiccups.
PMCID: PMC1739304  PMID: 15608002
2.  Differentiation of early hepatocellular carcinoma from benign hepatocellular nodules on gadoxetic acid-enhanced MRI 
The British Journal of Radiology  2012;85(1018):e837-e844.
To test new diagnostic criteria for the discrimination of early hepatocellular carcinoma (HCC) from benign hepatocellular nodules on gadoxetic acid-enhanced MRI (Gd-EOB-MRI).
We retrospectively analysed 34 patients with 29 surgically diagnosed early HCCs and 31 surgically diagnosed benign hepatocellular nodules. Two radiologists reviewed Gd-EOB-MRI, including diffusion-weighted imaging (DWI), and the signal intensity at each sequence, presence of arterial enhancement and washout were recorded. We composed new diagnostic criteria based on the lesion size and MRI findings, and then the diagnostic performance was compared with that of conventional imaging criteria with logistic regression and a generalised estimating equation method.
A size cut-off value (≥1.5 cm diameter) and MRI findings of T1 hypointensity, T2 hyperintensity, DWI hyperintensity on both low and high b-value images (b=50 and 800 s mm−2, respectively), arterial enhancement, late washout and hepatobiliary hypointensity were selected as the diagnostic criteria. When lesions were considered malignant if they satisfied three or more of the above criteria, the sensitivity was significantly higher than when making a diagnosis based on arterial enhancement and washout alone (58.6% vs 13.8%, respectively; p=0.0002), while the specificity was 100.0% for both criteria.
Our new diagnostic criteria on Gd-EOB-MRI may help to improve the discrimination of early HCC from benign hepatocellular nodules.
PMCID: PMC3474012  PMID: 22553295
3.  Pathological correlation with diffusion restriction on diffusion-weighted imaging in patients with pathological complete response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results 
The British Journal of Radiology  2012;85(1017):e566-e572.
The objective of this study was to assess causative pathological factors associated with diffusion restriction on diffusion-weighted imaging (DWI) in patients who achieved pathological complete response (pCR) after treatment with neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer.
In total, 43 patients with locally advanced rectal cancer (≥T3 or lymph node positive) who underwent neoadjuvant CRT, subsequent surgery and ultimately achieved pCR were enrolled. All patients underwent pre- and post-CRT 3.0 T rectal MRI with DWI. Two radiologists blinded to pathological staging reviewed pre- and post-CRT 3.0 T rectal MRI for the presence of diffusion restriction in the corresponding tumour areas on post-CRT DWI, with a third radiologist arbitrating any disagreement. The consensus of these findings was then correlated with pathological data such as intramural mucin and the degree of proctitis and mural fibrosis seen on surgical specimen. Additionally, the pre-CRT tumour volume was measured to define the effect of this variable on the degree of radiation proctitis and fibrosis, as well as the presence of intramural mucin.
Diffusion restriction occurred in 18 subjects (41.9%), while 25 subjects remained diffusion restriction-free (58.1%). The diffusion restriction group tended to have more severe proctitis and mural fibrosis when compared with non-diffusion restriction group (p<0.001). Intramural mucin was also more common in the diffusion restriction group (p=0.052). Higher pre-CRT tumour volumes were significantly predictive of the degree of proctitis (p=0.0247) and fibrosis (p=0.0445), but not the presence of intramural mucin (p=0.0944). Proctitis and mural fibrosis severity were also identified as independent pathological risk factors for diffusion restriction on multivariate analysis (p=0.0073 and 0.0011, respectively).
Both radiation-induced proctitis and fibrosis were significant and independent predictors of diffusion restriction in patients achieving pCR after treatment with neoadjuvant CRT for locally advanced rectal cancer, and pre-CRT tumour volume significantly affects both variables.
PMCID: PMC3487069  PMID: 22422387
4.  Contrast-enhanced MR cholangiography: comparison of Gd-EOB-DTPA and Mn-DPDP in healthy volunteers 
The British Journal of Radiology  2012;85(1017):1250-1254.
The purpose of this study was to compare the biliary enhancement dynamics of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid (Gd-EOB-DTPA) and mangafodipir trisodium (Mn-DPDP) for contrast-enhanced MR cholangiography (MRC) in healthy subjects.
15 healthy volunteers underwent MRI at 1.5 T with volumetric interpolated breath-hold examination sequence. Each volunteer was scanned once for each contrast agent. The signal-to-noise ratio (SNR) of the liver parenchyma and common hepatic duct (CHD) and the contrast-to-noise ratio (CNR) of CHD to liver parenchyma were evaluated and compared before and at several time points (5, 15, 30, 45, 60, 90, and 120 min) after injection of each agent.
SNR was significantly higher for Gd-EOB-DTPA than for Mn-DPDP in liver parenchyma after 5 min and in CHD after 15 min (p<0.05). CNR of CHD to liver parenchyma using Gd-EOB-DTPA showed an initial decrease at 5 min post-injection followed by a steep increase to a peak at 15 min post-injection. CNR using Mn-DPDP showed a steady increase to a peak at 15 min post-injection without an initial decrease. At 15 min, the value of CNR was significantly higher for Gd-EOB-DTPA than for Mn-DPDP (p<0.05).
For both contrast agents, CNR reached a peak at 15 min after contrast injection. At this time point, CNR of Gd-EOB-DTPA was significantly higher than that of Mn-DPDP. Therefore, Gd-EOB-DTPA may provide better contrast-enhanced MRC than Mn-DPDP at 15 min after contrast administration.
PMCID: PMC3487056  PMID: 22553292
5.  Decay of Impact after Self-Management Education for People with Chronic Illnesses: Changes in Anxiety and Depression over One Year 
PLoS ONE  2013;8(6):e65316.
In people with chronic illnesses, self-management education can reduce anxiety and depression. Those benefits, however, decay over time. Efforts have been made to prevent or minimize that “decay of impact”, but they have not been based on information about the decay’s characteristics, and they have failed. Here we show how the decay’s basic characteristics (prevalence, timing, and magnitude) can be quantified. Regarding anxiety and depression, we also report the prevalence, timing, and magnitude of the decay.
Adults with various chronic conditions participated in a self-management educational program (n = 369). Data were collected with the Hospital Anxiety and Depression Scale four times over one year. Using within-person effect sizes, we defined decay of impact as a decline of ≥0.5 standard deviations after improvement by at least the same amount. We also interpret the results using previously-set criteria for non-cases, possible cases, and probable cases.
Prevalence: On anxiety, decay occurred in 19% of the participants (70/369), and on depression it occurred in 24% (90/369). Timing: In about one third of those with decay, it began 3 months after the baseline measurement (6 weeks after the educational program ended). Magnitude: The median magnitudes of decay on anxiety and on depression were both 4 points, which was about 1 standard deviation. Early in the follow-up year, many participants with decay moved into less severe clinical categories (e.g., becoming non-cases). Later, many of them moved into more severe categories (e.g., becoming probable cases).
Decay of impact can be identified and quantified from within-person effect sizes. This decay occurs in about one fifth or more of this program’s participants. It can start soon after the program ends, and it is large enough to be clinically important. These findings can be used to plan interventions aimed at preventing or minimizing the decay of impact.
PMCID: PMC3681854  PMID: 23785418
6.  Association between Endocrine Disrupting Phenols in Colostrums and Maternal and Infant Health 
Bisphenol A (BPA) and alkylphenols (APs) are well-known endocrine disrupting chemicals (EDCs) which may threat the next generations' health. We performed biomonitoring of these phenols in colostrums to assess risk of the phenols in breast-fed neonates. Study subjects were the lactating mothers who delivered babies within 2 weeks (N = 325; 30.67 ± 3.45 years) and their neonates (N = 326; embryonic period, 39.1 ± 1.5 weeks). BPA, nonylphenol (NP), and octylphenol (OP) in colostrums were quantified with LC/MS/MS. Information for environmental exposure sources of the phenols was obtained by questionnaires. As results, median level of BPA in colostrums was 7.8 ng/mL, while most NP or OP was not detected. Regarding health risks of phenols, levels of total NP in colostrums were elevated among sick mothers with toxemia, thyroid disorders, gastritis, and so forth than health mothers (3.51 ± 4.98 versus 2.04 ± 3.71 ng/mL, P = 0.02). Dairy products intake and detergents use were positively correlated with total BPA levels (Ps < 0.05). In conclusion, we estimate most neonates who are exposed to BPA rather than NP or OP via colostrums and recommend continuous biomonitoring of the phenols to clarify their suspected health risk on neonates and pregnant or gestation mothers.
PMCID: PMC3662185  PMID: 23737772
7.  MRI features of serous oligocystic adenoma of the pancreas: differentiation from mucinous cystic neoplasm of the pancreas 
The British Journal of Radiology  2012;85(1013):571-576.
The purpose of this study was to describe the MRI features of the benign pancreatic neoplasm serous oligocystic adenoma (SOA) that differ from those of mucinous cystic neoplasm (MCN), a neoplasm with the potential for malignant degeneration.
Seven patients with SOA (seven women; mean age 36.6 years) and eight patients with MCN (eight women: mean age 39.9 years) were included. Several imaging features were reviewed: mass size, location, shape, wall thickness, cyst configuration (Type I, unilocular; Type II, multiple clustered cyst; Type III, cyst with internal septation) and signal intensity of the lesion with heterogeneity.
SOA lesions were smaller (3.4 cm) than those of MCN (9.3 cm) (p=0.023). The commonest lesion shape was lobulated (85.7%) for SOA, but oval (50.0%) or lobulated (37.5%) for MCN (p=0.015). The most common cyst configuration was Type II (85.7%) for SOA and Type III (75.0%) for MCN (p=0.008). Heterogeneity of each locule in T1 weighted images was visible in all cases of MCN, but in no case for SOA (p=0.004).
SOA could be differentiated from MCN by identifying the imaging features of lobulated contour with multiple clustered cyst configurations and homogeneity of each locule in T1 weighted MR images.
PMCID: PMC3479889  PMID: 21304008
9.  eIF5A isoforms and cancer: two brothers for two functions? 
Amino acids  2011;44(1):103-109.
Eukaryotic translation initiation factor 5A (eIF5A) is the only cellular protein that contains the unusual amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. The role of hypusine formation in the eIF5A protein in the regulation of cell proliferation and apoptosis is addressed in the present review. Moreover, vertebrates carry two genes that encode two eIF5A isoforms, eIF5A-1 and eIF5A-2, which, in humans, are 84% identical. However, the biological functions of these two isoforms may be significantly different. In fact, eIF5A-1 is demonstrable in most cells of different histogenesis, whereas eIF5A-2 protein is detectable only in certain human cancer cells or tissues, suggesting its role as a potential oncogene. In this review we focus our attention on the involvement of eIF5A-1 in the triggering of an apoptotic program and in the regulation of cell proliferation. In addition, the potential oncogenic role and prognostic significance of eIF5A-2 in the prediction of the survival of cancer patients is described. eIF5A-1 and/or the eIF5A-2 isoform may serve as a new molecular diagnostic or prognostic marker or as a molecular target for anti-cancer therapy.
PMCID: PMC3536922  PMID: 22139412
eIF5A isoform; Hypusine; Tissue transglutaminase; Cancer; Apoptosis; Prognostic markers; Hypusine synthesis inhibitors
10.  Acinar cell carcinoma with fatty change arising from the pancreas 
The British Journal of Radiology  2011;84(1008):e226-e228.
Acinar cell carcinoma of the pancreas is a rare malignant tumour developing from acinar cells, accounting for approximately 1% of pancreatic exocrine tumours. We experienced a case of an acinar cell carcinoma with fatty change. To the best of our knowledge, this is the first case report of an acinar cell carcinoma with fatty change in the clinical literature.
PMCID: PMC3473822  PMID: 22101587
11.  Reprogramming of the Tumor Microenvironment by Stromal Pten-regulated miR-320 
Nature Cell Biology  2011;14(2):159-167.
Phosphatase and tensin homolog deleted on chromosome ten (Pten) in stromal fibroblasts suppresses epithelial mammary tumors, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2, are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumor angiogenesis and tumor cell invasion. Expression of the Pten-miR-320-Ets2 regulated secretome distinguished human normal breast stroma from tumor stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumor suppressor axis that acts in stromal fibroblasts to reprogram the tumor microenvironment and curtail tumor progression.
PMCID: PMC3271169  PMID: 22179046
13.  PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation 
Cell Death and Differentiation  2010;18(4):666-677.
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTEN-proficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.
PMCID: PMC3131905  PMID: 21072054
premature senescence; apoptosis; PTEN; glioma
15.  Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy 
Cell Death and Differentiation  2010;18(2):350-361.
The sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) have recently been implicated in autophagy. In this study, we report that depletion of sphingosine-1-phosphate phosphohydrolase-1 (SPP1), an endoplasmic reticulum (ER)-resident enzyme that specifically dephosphorylates S1P, induced autophagy. Although the mammalian target of rapamycin and class III phosphoinositide 3-kinase/Beclin-1 pathways were not involved and this autophagy was p53 independent, C/EBP homologous protein, BiP, and phospho-eucaryotic translation initiation factor-2α, and cleavage of procaspases 2 and 4, downstream targets of ER stress, were increased after SPP1 depletion. Autophagy was suppressed by depletion of protein kinase regulated by RNA-like ER kinase (PERK), inositol-requiring transmembrane kinase/endonuclease-1α, or activating transcription factor 6, three sensors of the unfolded protein response (UPR) to ER stress. Autophagy triggered by downregulation of SPP1 did not lead to apoptosis but rather stimulated, in a PERK dependent manner, the survival signal Akt, whose inhibition then sensitized cells to apoptosis. Although depletion of SPP1 increased intracellular levels of S1P and its secretion, activation of cell surface S1P receptors did not induce autophagy. Nevertheless, increases in intracellular pools of S1P, but not dihydro-S1P, induced autophagy and ER stress. Thus, SPP1, by regulating intracellular S1P homeostasis, can control the UPR and ER stress-induced autophagy.
PMCID: PMC3131882  PMID: 20798685
sphingosine-1-phosphate phosphatase-1; autophagy; ER stress; apoptosis; Akt
16.  Antibody Colocalization Microarray: A Scalable Technology for Multiplex Protein Analysis in Complex Samples* 
Molecular & Cellular Proteomics : MCP  2011;11(4):M111.011460.
DNA microarrays were rapidly scaled up from 256 to 6.5 million targets, and although antibody microarrays were proposed earlier, sensitive multiplex sandwich assays have only been scaled up to a few tens of targets. Cross-reactivity, arising because detection antibodies are mixed, is a known weakness of multiplex sandwich assays that is mitigated by lengthy optimization. Here, we introduce (1) vulnerability as a metric for assays. The vulnerability of multiplex sandwich assays to cross-reactivity increases quadratically with the number of targets, and together with experimental results, substantiates that scaling up of multiplex sandwich assays is unfeasible. We propose (2) a novel concept for multiplexing without mixing named antibody colocalization microarray (ACM). In ACMs, both capture and detection antibodies are physically colocalized by spotting to the same two-dimensional coordinate. Following spotting of the capture antibodies, the chip is removed from the arrayer, incubated with the sample, placed back onto the arrayer and then spotted with the detection antibodies. ACMs with up to 50 targets were produced, along with a binding curve for each protein. The ACM was validated by comparing it to ELISA and to a small-scale, conventional multiplex sandwich assay (MSA). Using ACMs, proteins in the serum of breast cancer patients and healthy controls were quantified, and six candidate biomarkers identified. Our results indicate that ACMs are sensitive, robust, and scalable.
PMCID: PMC3322566  PMID: 22171321
17.  MRI findings of uncommon non-hepatocyte origin primary liver tumours with pathological correlation 
The British Journal of Radiology  2010;83(996):1080-1086.
The objective of this article was to illustrate the MRI findings of uncommon non-hepatocyte origin primary liver tumours, correlate them with the pathological features and discuss differential diagnoses. In conclusion, the MRI findings of uncommon benign and malignant non-hepatocyte-origin primary liver tumours vary. Awareness of characteristic MRI features can aid differential diagnosis and prevent unnecessary surgery.
PMCID: PMC3473623  PMID: 20923912
19.  Combination of high-resolution susceptibility-weighted imaging and the apparent diffusion coefficient: added value to brain tumour imaging and clinical feasibility of non-contrast MRI at 3 T 
The British Journal of Radiology  2010;83(990):466-475.
The purpose of this study was to determine the benefit of high-resolution susceptibility-weighted imaging and the apparent diffusion coefficient for brain tumour imaging, and to assess the clinical feasibility of using a non-contrast MR protocol at 3 T. 73 patients with intra-axial tumours were enrolled into the study. Two experienced neuroradiologists reviewed three MRI sessions: (i) a non-contrast protocol including high-resolution susceptibility-weighted images and apparent diffusion coefficient; (ii) a contrast protocol including MR perfusion images; and (iii) combined contrast and non-contrast protocols. The two observers categorised tumours as glial or non-glial tumours, and then subcategorised the gliomas into low-grade or high-grade tumours. For semi-quantitative analysis, a scoring system based on the degree of intra-tumoral susceptibility signals and the visual apparent diffusion coefficient was used. The two observers diagnosed accurate tumour pathology in 52 (71%) of 73 tumours in the first review, 55 (75%) of 73 tumours in the second review and 61 (84%) of 73 tumours in the third review. The addition of the non-contrast protocol to the contrast protocol significantly differentiated glioblastoma multiforme and metastatic tumours, which was not possible with the contrast protocol alone. The sensitivity, specificity, positive predictive value and negative predictive value for glioma grading with the non-contrast protocol were 83.2%, 100%, 100% and 79.3%, respectively. The addition of both high-resolution susceptibility-weighted imaging and the apparent diffusion coefficient improved the diagnostic performance of the contrast MR protocol for brain tumour imaging and could be feasible in selected patients who cannot tolerate a contrast agent.
PMCID: PMC3473590  PMID: 19690076
20.  Medulla compression caused by vertebral artery dolichoectasia 
BMJ Case Reports  2009;2009:bcr2007123885.
PMCID: PMC3105908  PMID: 21687294
21.  Functional significance of eIF5A and its hypusine modification in eukaryotes 
Amino acids  2009;38(2):491-500.
The unusual basic amino acid, hypusine [Nε-(4-amino-2-hydroxybutyl)-lysine], is a modified lysine with the addition of the 4-aminobutyl moiety from the polyamine spermidine. This naturally occurring amino acid is a product of a unique posttranslational modification that occurs in only one cellular protein, eukaryotic translation initiation factor 5A (eIF5A, eIF-5A). Hypusine is synthesized exclusively in this protein by two sequential enzymatic steps involving deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The deoxyhypusine/hypusine synthetic pathway has evolved in archaea and eukaryotes, and eIF5A, DHS and DOHH are highly conserved suggesting a vital cellular function of eIF5A. Gene disruption and mutation studies in yeast and higher eukaryotes have provided valuable information on the essential nature of eIF5A and the deoxyhypusine/hypusine modification in cell growth and in protein synthesis. In view of the extraordinary specificity and functional significance of hypusine-containing eIF5A in mammalian cell proliferation, eIF5A and the hypusine biosynthetic enzymes are novel potential targets for intervention in aberrant cell proliferation.
PMCID: PMC2829442  PMID: 19997760
Hypusine; eIF5A; Posttranslational modification; Polyamine; Deoxyhypusine synthase; Deoxyhypusine hydroxylase; Gene inactivation
22.  Steroid-Sparing effects of pentoxifylline in pulmonary sarcoidosis 
Agents that target pro-inflammatory cytokines may be useful in pulmonary sarcoidosis.
To determine effectiveness of a non-selective cyclic nucleotide phosphodiesterase (PDE) inhibitor, pentoxifylline (POF).
Randomized, double-blind, placebo-controlled trial
Clinical Research Center, National Institutes of Health.
27 patients with biopsy-confirmed pulmonary sarcoidosis receiving prednisone.
Placebo or POF (1200-2000 mg/day) for 10 months, as prednisone was tapered.
Primary endpoints: sustained improvement in two or more pulmonary function parameters, or a combination of one pulmonary function parameter and dyspnea.
Except for one patient, primary endpoints were not reached in POF-treated patients. Therefore, a post hoc analysis was performed. The observed relative risk reduction for flares associated with POF treatment was 54.9% (95% CI 0.21, 0.89) and the absolute risk reduction was 50.6% (95% CI 0.22, 0.80). Compared to placebo treatment, in the POF group, the mean prednisone dose was lower at 8 and 10 months (p = 0.007 and 0.01 respectively), and there was a trend towards less prednisone usage over the entire study period (p = 0.053), as determined by cumulative change analysis.
Although our exploratory post hoc analysis suggested that POF reduced flares and had steroid-sparing effects, given the study limitations, definitive conclusions cannot be drawn regarding the efficacy of POF in pulmonary sarcoidosis. In addition, gastrointestinal side-effects, at the doses used, would seem to limit the use of POF in treating pulmonary sarcoidosis. Overall, however, this trial may provide a basis for using more specific, better-tolerated, PDE inhibitors in future clinical trials.
PMCID: PMC2946799  PMID: 20560292
pentoxifylline; phosphodiesterase; sarcoidosis; steroid-sparing; pulmonary function
23.  Electron Transfer Dissociation on Small Intact Proteins in an Ultra High Resolution Quadrupole Time of Flight Mass Spectrometer 
Electron Transfer Dissociation (ETD) has become a powerful technique for characterizing post translational modifications of proteins. Requiring interaction of both, analyte as well as ETD reagent ions, ETD is most commonly implemented in trapping instruments like 2D or 3D ion traps, providing low acquisition speed and mass accuracy. In contrast, Orthogonal Time of Flight (OTOF) instruments feature very high acquisition speed, mass accuracy, and in-spectra dynamic range. We present an instrument merging the trapping technique of ETD with an ultra high resolution quadrupole TOF, providing a resolution of 40,000, a mass accuracy <2ppm and an LC compatible spectra rate. The instrument used for this work is a Bruker ETD-maXis quadrupole TOF. ETD reagent anions were generated in an nCI source and are orthogonally injected between a pair of octapoles; which along with the nCI source were adapted from amaZon ETD ion trap. Reagent and analyte ions were mass selectively transmitted through a mass resolving quad and trapped in a hexapole collision cell. After the ETD reaction, product ions are transferred to a cooling cell where they are stored and extracted to the TOF analyzer. While ions are extracted, the next ETD experiment is ongoing in the collision cell thus maximizing duty cycle. ETD MS/MS data of intact proteins show a very complex mixture of ETD product ions, where the high resolution and mass accuracy capability of the TOF instrument was more than sufficient for protein identification with Mascot data base search of the intact protein. The work thus far shows a novel ultra-high resolution quadrupole TOF that is capable of rapid ETD experiments with sufficient resolving power for ETD MS/MS analysis of small intact proteins. We will present ETD MS/MS of proteins samples (ubiquitin, cytochrome C, beta-casein and carbonic anhydrase) resulting in sequence coverage of up to 90%.
PMCID: PMC2918003
24.  Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients 
British Journal of Cancer  2009;100(6):894-900.
In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM.
PMCID: PMC2661774  PMID: 19240719
trastuzumab; brain metastasis; HER2-overexpressing breast cancer; extracranial disease control
25.  Weekly full-dose gemcitabine and single-dose cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer 
British Journal of Cancer  2008;98(5):881-887.
The aim of this study was to evaluate the efficacy and the toxicity of a full dose of gemcitabine and a single dose of cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Forty-one patients with locally advanced pancreatic cancer were enrolled. Patients received gemcitabine (1000 mg m−2 on days 1, 8, 15, 29, and 36) and cisplatin (70 mg m−2 on days 1 and 29) with concurrent radiotherapy (45 Gy in 25 fractions). Treatment was completed in 38 out of 41 patients (92.7%). The overall response rate was 24.4% (two complete and eight partial). Six patients (14.6%) underwent definite pancreatic resection and four had negative surgical margins. The intention of the treatment analysis showed that the median survival time and median time to tumour progression were 16.7 and 8.9 months. The 1- and 2-year survival rates were 63.3 and 27.9%, respectively. Overall survival was significantly longer in the low baseline CA19-9 group and therapeutic responders. Toxicities were tolerable and successfully managed by conservative treatments. The therapeutic scheme of a weekly full dose of gemcitabine and a single dose of cisplatin combined with external radiation is effective and might prolong the survival of patients with locally advanced pancreatic cancer.
PMCID: PMC2266862  PMID: 18301403
pancreatic cancer; gemcitabine; cisplatin; concurrent chemoradiotherapy

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