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1.  Radiosensitivity of pimonidazole-unlabelled intratumour quiescent cell population to γ-rays, accelerated carbon ion beams and boron neutron capture reaction 
The British Journal of Radiology  2013;86(1021):20120302.
Objective
To detect the radiosensitivity of intratumour quiescent (Q) cells unlabelled with pimonidazole to accelerated carbon ion beams and the boron neutron capture reaction (BNCR).
Methods
EL4 tumour-bearing C57BL/J mice received 5-bromo-29-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. After the administration of pimonidazole, tumours were irradiated with c-rays, accelerated carbon ion beams or reactor neutron beams with the prior administration of a 10B-carrier. Responses of intratumour Q and total (P+Q) cell populations were assessed based on frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole-unlabelled tumour cells was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole.
Results
Following c-ray irradiation, the pimonidazole-unlabelled tumour cell fraction showed significantly enhanced radiosensitivity compared with the whole tumour cell fraction, more remarkably in the Q than total cell populations. However, a significantly greater decrease in radiosensitivity in the pimonidazole-unlabelled cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed among the Q than total cells. These changes in radiosensitivity were suppressed following carbon ion beam and neutron beam-only irradiaton. In the BNCR, the use of a 10B-carrier, especially L-para-boronophenylalanine-10B, enhanced the sensitivity of the pimonidazole-unlabelled cells more clearly in the Q than total cells.
Conclusion
The radiosensitivity of the pimonidazole-unlabelled cell fraction depends on the quality of radiation delivered and characteristics of the 10B-carrier used in the BNCR.
Advances in knowledge
The pimonidazole-unlabelled subfraction of Q tumour cells may be a critical target in tumour control.
doi:10.1259/bjr.20120302
PMCID: PMC3615400  PMID: 23255546
2.  Effects of employing a 10B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy 
The British Journal of Radiology  2012;85(1011):249-258.
Objectives
To evaluate the effects of employing a 10B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy (BNCT) by measuring the response of intratumour quiescent (Q) cells.
Methods
B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumours received reactor thermal neutron beam irradiation following the administration of a 10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)] in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation.
Results
BPA-BNCT increased the sensitivity of the total tumour cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a 10B–carrier, MTH enhanced the sensitivity of the Q cell population. Without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with nicotinamide treatment, showed the potential to reduce the number of metastases more than BSH-BNCT.
Conclusion
BSH-BNCT in combination with MTH improves local tumour control, while BPA-BNCT in combination with nicotinamide may reduce the number of lung metastases.
doi:10.1259/bjr/20974899
PMCID: PMC3473983  PMID: 22391496
3.  Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential 
The British Journal of Radiology  2011;84(1008):1131-1138.
Objectives
The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours.
Methods
B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation following treatment with the acute hypoxia-releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation.
Results
3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to γ-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without γ-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment.
Conclusion
Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide.
doi:10.1259/bjr/38457938
PMCID: PMC3473837  PMID: 21586505
4.  Significance of manipulating tumour hypoxia and radiation dose rate in terms of local tumour response and lung metastatic potential, referring to the response of quiescent cell populations 
The British Journal of Radiology  2010;83(993):776-784.
The purpose of this study was to evaluate the influence of manipulating intratumour oxygenation status and radiation dose rate on local tumour response and lung metastases following radiotherapy, referring to the response of quiescent cell populations within irradiated tumours. B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation at high dose rate (HDR) or reduced dose rate (RDR) following treatment with the acute hypoxia-releasing agent nicotinamide or local hyperthermia at mild temperatures (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the quiescent (Q) and total (proliferating + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Following HDR irradiation, nicotinamide and MTH enhanced the sensitivity of the total and Q-cell populations, respectively. The decrease in sensitivity at RDR irradiation compared with HDR irradiation was slightly inhibited by MTH, especially in Q cells. Without γ-ray irradiation, nicotinamide treatment tended to reduce the number of lung metastases. With γ-rays, in combination with nicotinamide or MTH, especially the former, HDR irradiation decreased the number of metastases more remarkably than RDR irradiation. Manipulating both tumour hypoxia and irradiation dose rate have the potential to influence lung metastasis. The combination with the acute hypoxia-releasing agent nicotinamide may be more promising in HDR than RDR irradiation in terms of reducing the number of lung metastases.
doi:10.1259/bjr/57015642
PMCID: PMC3473411  PMID: 20739345
5.  Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer 
British Journal of Cancer  2007;96(2):277-283.
High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (P<0.01 and P<0.05, respectively). The TS- and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (P<0.0001 and P<0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy.
doi:10.1038/sj.bjc.6603546
PMCID: PMC2360001  PMID: 17211470
thymidylate synthase; p53; S-1; cisplatin; gastric cancer
6.  Endovascular GDC Treatment of an Idiopathic Carotid-Cavernous Fistula Caused by Aneurysmal Rupture of the Intra-Cavernous Carotid Artery 
Interventional Neuroradiology  2006;12(Suppl 1):174-177.
Summary
Aneurysmal rupture of the intra-cavernous carotid artery may cause idiopathic carotid-cavernous fistula (CCF), and the treatment choice for occluding shunting fistula in this type of CCF is an endovascular approach using detachable balloons. However, little has been reported on treating such lesions with the intra-aneurysmal embolization using Guglielmi detachable coils (GDCs). To our knowledge, ours is the first reported case of successful treatment by selective intra-fistula and intra-aneurysmal embolization with GDCs. A 74-year-old woman exhibited proptosis and chemosis of her left eye over a period of one month. Symptoms of double vision in conversion and pulsatile murmur in her left eye were also noted. Angiography revealed an intra-cavernous aneurysm of the left internal carotid artery (ICA) with a shunting fistula, which drained into the dilated cavernous sinus, superior orbital vein (SOV), superior petrosal sinus, inferior petrosal sinus, and pterygoid plexus. We thought the fistula would occlude by intra-aneurysmal embolization, but we had no confidence of tight packing of the aneurysm since the aneurismal neck was relatively wide. So, we embolized the venous side of the shunting fistula and then the dome of the aneurysm with GDCs. Immediately after the operation, her symptoms and signs were ameliorated, and complete occlusion of the CCF was observed on long-term follow-up. We suggest selective intrafistula and intra-aneurysmal embolization with GDCs as an alternative method of treatment of idiopathic CCF originating from aneurysmal rupture of the intra-cavernous carotid artery.
PMCID: PMC3387948  PMID: 20569626
idiopathic CCF; aneurysm; GDC
7.  Insulin therapy in burn patients does not contribute to hepatic triglyceride production. 
Journal of Clinical Investigation  1998;101(10):2233-2239.
Lipid kinetics were studied in six severely burned patients who were treated with a high dose of exogenous insulin plus glucose to promote protein metabolism. The patients were 20+/-2-yr-old (SD) with 63+/-8% total body surface area burned. They were studied in a randomized order (a) in the fed state on the seventh day of a control period (C) of continuous high-carbohydrate enteral feeding alone, and (b) on the seventh day of enteral feeding plus exogenous insulin (200 pmol/h = 28 U/h) with extra glucose given as needed to avoid hypoglycemia (I+G). Despite a glucose delivery rate approximately 100% in excess of energy requirements, the following lipid parameters were unchanged: (a) total hepatic VLDL triglyceride (TG) secretion rate (0.165+/-0.138 [C] vs. 0.154+/- 0.138 mmol/kg . d-1 [I+G]), (b) plasma TG concentration (1.58+/-0.66 [C] vs. 1. 36+/-0.41 mmol/liter [I+G]), and (c) plasma VLDL TG concentration (0. 68+/-0.79 [C] vs. 0.67+/- 0.63 mmol/liter [I+G]). Instead, the high-carbohydrate delivery in conjunction with insulin therapy increased the proportion of de novo-synthesized palmitate in VLDL TG from 13+/-5% (C) to 34+/-14% (I+G), with a corresponding decreased amount of palmitate from lipolysis. In association with the doubling of the secretion rate of de novo-synthesized fatty acid (FA) in VLDL TG during insulin therapy (P > 0.5), the relative amount of palmitate and stearate increased from 35+/-5 to 44+/-8% and 4+/-1 to 7+/-2%, respectively, in VLDL TG, while the relative concentration of oleate and linoleate decreased from 43+/-5 to 37+/-6% and 8+/-4% to 2+/-2%, respectively. A 15-fold increase in plasma insulin concentration did not change the rate of release of FA into plasma (8.22+/-2.86 [C] vs. 8.72+/-6.68 mmol/kg.d-1 [I+G]. The peripheral release of FA represents a far greater potential for hepatic lipid accumulation in burn patients than the endogenous hepatic fat synthesis, even during excessive carbohydrate intake in conjunction with insulin therapy.
PMCID: PMC508811  PMID: 9593779
8.  Transformation of Escherichia coli with a large plasmid of Acidiphilium multivorum AIU 301 encoding arsenic resistance. 
Acidiphilium multivorum AIU 301 isolated from acid mineral water had strong arsenic resistance. This bacterium harbored a number of plasmids with different molecular sizes. A plasmid of 56 kbp, named pKW301, was isolated from A. multivorum AIU 301. When pKW301 was transferred into Escherichia coli JM109 by electroporation, an E. coli transformant carrying pKW301 exhibited resistance to sodium arsenite, sodium arsenate, and mercuric (II) chloride.
PMCID: PMC168498  PMID: 9143138
9.  Naming difficulties in alexia with agraphia for kanji after a left posterior inferior temporal lesion. 
The case is described of a patient with alexia and agraphia for kanji, and severe anomia after a subcortical haemorrhage in the left posterior inferior temporal area. Magnetic resonance imaging at four months after onset showed a lesion in the inferior temporal and fusiform gyri, extending from the temporo-occipital junction toward the anterior third of the temporal lobe. Comparison with other reported cases of alexia with agraphia and anomia made it clear that when accompanied by severe anomia, the lesions extended either forward to the anterior part of the middle temporal gyrus or medially to the parahippocampal gyrus. It is suggested that the disconnection of association fibres between the parahippocampal, fusiform, middle, and inferior temporal gyri, especially between the parahippocampal gyrus and the other temporal gyri, or the cortical damage to the posterior part of these gyri is essential for the production of anomia.
Images
PMCID: PMC1072925  PMID: 8201334
10.  Short-term effects of tumor necrosis factor on energy and substrate metabolism in dogs. 
Journal of Clinical Investigation  1993;91(6):2437-2445.
In vivo short-term effects of recombinant human TNF-alpha on lipolysis, FFA flux, fat oxidation, triglyceride-fatty acid cycling, and glucose kinetics were evaluated with stable isotopic tracers and indirect calorimetry along with monitoring of hemodynamic parameters in fasted dogs. High-dose TNF infusion (10 micrograms/kg) caused a fall in mean arterial pressure (P < 0.01), pulmonary arterial pressure (P < 0.001), and cardiac index (CI) (P < 0.05). The rate of appearance of glycerol (Ra glycerol) and the rate of appearance of FFA (Ra FFA) were decreased by 20% (P < 0.05) and by 42% (P < 0.01), respectively. Total fat oxidation fell by 23% (P < 0.05). In contrast, TNF infusion significantly increased glucose production by 13% (P < 0.05) and metabolic clearance rate of glucose by 25% (P < 0.01). However, TNF infusion did not change energy expenditure. Low-dose TNF infusion (3.5 micrograms/kg) caused changes similar in all respects, except magnitude, to the high-dose effects. There was a significant correlation between percent change of CI (delta CI) and percent change of rate of appearance of palmitate (Ra palmitate; delta Ra palmitate) (P < 0.0001, r = 0.69), Ra FFA (delta Ra FFA) (P < 0.0001, r = 0.60), and Ra glycerol (delta Ra glycerol) (P < 0.0329, r = 0.36). The correlation between delta CI and delta Ra palmitate was greater than the correlation between delta CI and delta Ra glycerol (P = 0.028). We conclude that the acute response to TNF causes a shift towards carbohydrate as an energy substrate in a dose-dependent manner by both decreasing the availability of FFAs and increasing glucose production.
PMCID: PMC443303  PMID: 8514856
11.  Nucleotide sequence and characterization of a carbenicillin-hydrolyzing penicillinase gene from Proteus mirabilis. 
Journal of Bacteriology  1991;173(21):7038-7041.
The structural gene of a carbenicillinase was cloned from the chromosomal DNA of Proteus mirabilis GN79. This gene codes for a protein of 270 amino acids. Alignment of the amino acid sequence with those of known beta-lactamases revealed that the enzyme is a novel class A beta-lactamase with a unique conserved triad, RTG. By using a DNA fragment of the structural gene, a lack of cross hybridization was confirmed between the DNA probe and total DNAs from natural isolates of P. mirabilis, suggesting that the carbenicillinase may not be a species-specific beta-lactamase of P. mirabilis.
Images
PMCID: PMC209063  PMID: 1840585
12.  Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis 
Clinical Genetics  2012;82(6):514-520.
Human noggin (NOG) is a responsible gene for multiple synostosis syndrome (SYNS1) and proximal symphalangism (SYM1), two conditions that are recently known to be within a wider range of clinical manifestations of stapes ankylosis with symphalangism. This study was performed to determine the range of phenotype caused by NOG mutations, using Japanese patients with various phenotypes including sporadic inherited SYM1, dominantly inherited SYM1, stapes ankylosis with broad thumb and toes (Teunissen and Cremer syndrome). In addition, 33 patients with typical otosclerosis (without symphalangism) were studied. Direct sequencing analysis disclosed three novel mutations of the NOG gene in three SYM1 families. None of the otosclerosis patients without symphalangism had NOG mutations, indicating that NOG mutations may be restrictively found within patients with various skeletal abnormalities. These results together with the literature review indicated that there are no clear genotype–phenotype correlations for NOG mutations. With regard to surgical outcome, most of the patients in these three families with NOG mutations showed remarkable air–bone gap recovery after stapes surgery. Molecular genetic testing is useful to differentiate syndromic stapes ankylosis from otosclerosis, and even mild skeletal anomalies can be a diagnostic indicator of NOG-associated disease.
doi:10.1111/j.1399-0004.2011.01831.x
PMCID: PMC3532604  PMID: 22288654
otosclerosis; stapes ankylosis; stapes ankylosis with broad; SYM1; symphalangism; Teunissen and Cremer syndrome; thumb and toes
13.  Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection 
Journal of Viral Hepatitis  2012;19(2):e112-e119.
Background: Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied. Methods: In a phase 1b study in Japan, 10 treatment-naïve patients infected with hepatitis C virus genotype 1b with high viral load (>5 log10 IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir. Results: Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log10 decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala156-substituted variants occurred in eight patients, and only one patient showed end-of-treatment response. The selected variants reverted to the wild-type during the 24-week follow-up period. Conclusion: Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct-acting antiviral agents.
doi:10.1111/j.1365-2893.2011.01514.x
PMCID: PMC3584515  PMID: 22239508
genotype 1b; pharmacokinetics; resistant variants; telaprevir monotherapy; tolerability

Results 1-13 (13)