Inhibitory effect of butylated hydroxyanisole administration on pancreatic carcinogenesis in Syrian hamsters initiated with N-nitrosobis(2-oxopropyl)amine

The modifying potential of butylated bydroxyanisole (BHA) administrationon pancreatic carcinogenesis was evaluated in 70 female Syriangolden hamsters. Groups of animals received saline, 70 mg/kgbody weight of N-nitrosobis(2-oxopropyl)-amine (BOP) or 70 mg/kgplus 20 mg/kg body weight of BOP followed by basal diet or dietcontaining 2% BHA from week 3. Although the body weights ofhamsters receiving the 2% BHA supplement decreased, caloricrestriction was not observed. All hamsters were killed at week18 and histo-pathologically examined for lesion development.The incidences of pancreatic carcinomas in hamsters receiving70 mg/kg plus 20 mg/kg body weight of carcinogen followed by2% BHA was 7.1%, significantly lower than the 64.3% evidentin hamsters given the same doses of BOP followed by basal diet.The total numbers of pancreatic lesions including carcinomas,atypical ductal hyperplasias and ductal hyperplasias and ductularproliferations in the liver were also significantly decreasedin animals receiving BOP followed by 2% BHA. The results thusindicate that both pancreatic and cholangiocellular carcinogenesisinitiated by BOP in Syrian hamsters can be inhibited by 2% BHAtreatment for a relatively short experimental period.     

Long-term follow-up of radiosurgically treated arteriovenous malformations in children: report of nine cases.

Long-term follow-up results of nine children treated for cerebral arteriovenous malformation with a gamma unit are presented. Complete nidus obliteration was angiographically confirmed in six cases and significant decreases in arteriovenous malformation size were observed in the other three. There were no radiation-related deteriorations in physical or mental development. In seven patients who underwent endocrinological examination more than 3 years after irradiation, five were normal and the other two showed only low serum adrenocorticotropic hormone levels, which, however, did not necessitate replacement therapy. Neurodiagnostic imaging follow-up studies revealed no radiation-induced lesions in any of the nine cases.     

Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors.

PURPOSE: The histological diagnosis of human gliomas is of great importance for estimating patient prognosis and guiding therapy but suffers from being subjective and, therefore, variable. We hypothesized that molecular genetic analysis could provide a more objective means to classify tumors and, thus, reduce diagnostic variability. EXPERIMENTAL DESIGN: We performed molecular genetic analysis on 91 nonselected gliomas for 1p, 19q, 10q, TP53, epidermal growth factor receptor, and cyclin-dependent kinase 4 abnormalities and compared with the consensus diagnoses established among four independent neuropathologists. RESULTS: There were six astrocytomas, seven anaplastic astrocytomas, 45 glioblastomas, 21 oligodendrogliomas, eight anaplastic oligodendrogliomas, three oligoastrocytomas, and one anaplastic oligoastrocytoma. Twenty-nine cases had either 1p or 19qloss of heterozygosity (LOH) while retaining both copies of 10q, of which 25 (86%) were histologically oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, or anaplastic oligoastrocytoma. As for the oligodendroglial tumors, unanimous agreement of the initial diagnoses was almost restricted to those cases with combined 1p/19qLOH, whereas all nine tumors without 1p loss initially received variable diagnoses. Interestingly, TP53 mutation was inversely related to 1pLOH in all gliomas (P = 0.0003) but not 19qLOH (P = 0.15). CONCLUSIONS: These data demonstrate that molecular genetic analysis of 1p/19q/10q/TP53 has significant diagnostic value, especially in detecting oligodendroglial tumors. In addition, 1pLOH and TP53 mutations in gliomas may be markers of oligodendroglial and astrocytic pathways, respectively, which may separate gliomas with the same histological diagnosis, especially oligodendroglial tumors and glioblastomas. Testing for those molecular genetic alterations would be essential to obtain more homogeneous sets of gliomas for the future clinical studies.     

Inhibition of experimental pulmonary metastasis by controlling biodistribution of catalase in mice

In a previous study, we showed that targeted delivery of bovine liver catalase to hepatocytes by direct galactosylation augmented the inhibitory effect of the enzyme on experimental hepatic metastasis of colon carcinoma cells (unpublished data). Here, we examined the ability of catalase to inhibit tumor metastasis to the lung by controlling its biodistribution. Four types of catalase derivative, Gal-CAT, Man-CAT, Suc-CAT and PEG-CAT, were synthesized. Experimental pulmonary metastasis was induced in mice by i.v. injection of 1 x 10(5) colon 26 tumor cells. An i.v. injection of catalase (35,000 units/kg) partially, but significantly, decreased the number of colonies in the lung 2 weeks after tumor injection, from 93 +/- 29 (saline injection) to 63 +/- 23 (p < 0.01). Suc-CAT, Man-CAT and Gal-CAT showed effects similar to those of catalase on the number of colonies. However, PEG-CAT greatly inhibited pulmonary metastasis to 22 +/- 11 (p < 0.001). Furthermore, s.c. injection of catalase also greatly inhibited metastasis (11 +/- 6, p < 0.001). Neither inactivated catalase nor BSA showed any effects on the number of metastatic colonies, indicating that the enzymatic activity of catalase to detoxify H(2)O(2) is the critical factor inhibiting metastasis. (111)In-PEG-CAT showed a sustained concentration in plasma, whereas s.c.-injected (111)In-catalase was slowly absorbed from the injection site. These results suggest that retention of catalase activity in the circulation is a promising approach to inhibit pulmonary metastasis.     

Examination of Purification Methods and Development of Intravitreal Injection of Triamcinolone Acetonide

Purpose

Intravitreal injection of triamcinolone acetonide (TA) is used in ophthalmic treatment, but the reliability of commercially available TA preparations has still not been established. We evaluated two previously reported purification methods, and developed a more reliable TA injection which can be prepared in a hospital pharmacy.

Methods

We tested the two methods previously reported for purifying commercial TA preparations, the sedimentation and the filtration and backflushing methods. We developed a new TA injection made of pure TA suspended in 0.5% sodium hyaluronate. We measured the TA content in each preparation by high-performance liquid chromatography to evaluate the three methods.

Results

In the sedimentation purification method, the TA content of a nominal 4-mg preparation varied from 1.43 to 7.37?mg, and the average recovery rate was 91.6%. In the filtration and backflushing method, TA content was 0.10–10.33?mg and recovery was 59.5%. In the TA injection we developed, the mean TA content was 102.5% (SD, 0.24; CV, 2.9%). The stability of this preparation was 99% after sterilization, and 97% after 3 months of storage.

Conclusions

The results of our investigation showed that the purification methods used for commercial preparations are simple and easy but not precise enough for an intravitreal injection. In contrast, the TA injection prepared by our method is reliable, stable, and safe enough for clinical use. Jpn J Ophthalmol 2005;49:384–387 © Japanese Ophthalmological Society 2005     

Perception in relation to a potential influenza pandemic among healthcare workers in Japan: implications for preparedness

Due to the potential for an influenza pandemic, preparedness for infection control in healthcare settings is essential from the standpoint of occupational health for healthcare workers. We conducted questionnaire surveys among Japanese hospitals to assess preparedness at the individual and institutional levels and their inter-relationship. Questionnaires were administered at 7 tertiary hospitals in Japan during the spring of 2006. We analyzed 7,378 individual responses of the 10,746 questionnaires administered and all seven institutional responses by hospital infection control committees. Healthcare workers assigned low importance to personal protective equipment and showed mixed attitudes (anxious but accepting) to the potential risk. Institutional gaps existed in preparedness across hospitals and most hospitals lacked the specificity to cope with a pandemic. A higher level of institutional preparedness, as determined by expertise as well as general and specific countermeasures, was an important predictor of individual recognition of preventive measures, perception of institutional measures, and attitude toward coping with risk. A higher level of institutional preparedness stood out to be an important predictor of individual preparedness. Considering the risk of a future influenza pandemic, hospitals should improve preparedness at all levels.     

Interaction of dietary protein differing in sulfur amino acid content and pectin on bile acid conjugation in immature and mature rats

Rapidly growing immature (4-wk-old) and slowly growing mature (15-wk-old) rats were fed fiber-free or 10 g/100 g pectin diets containing various proteins differing in the sulfur amino acid content for 30-32 d. Soybean protein, casein, whole egg protein and egg albumen were used at the nitrogen level of 2.7 g/100 g diet. These experimental diets contained 0.354, 0.540, 0.945 and 1.22 g sulfur amino acids/100 g, respectively. In the rats fed fiber-free diets, a substantial quantity of glycine-conjugated bile acids was detected in the bile of immature rats fed soybean protein and casein (73 and 25% of total bile acids, respectively), but not in the other groups (less than 13%). Dietary pectin increased bile acid excretion both in immature (48-77%) and mature (34-114%) rats irrespective of the protein source, except in immature rats fed egg albumen and mature rats fed whole egg protein. Because a pectin-dependent increase in bile acid excretion was essentially attributed to the increase in glycine-conjugates, this dietary fiber significantly increased the ratio of glycine-conjugates to taurine-conjugates (2.4- to 6.5-fold). This increase was accompanied by a 40-50% decrease in the concentration of liver taurine, except in immature rats fed soybean protein and egg albumen. However, there was no consistent relationship between the extent of taurine conjugation and the activity of liver cysteine dioxygenase, one of the rate-limiting enzymes in taurine synthesis.     

An epidermal growth factor-like toxin and two sodium channel toxins from the sea anemone Stichodactyla gigantea.

Three peptide toxins (gigantoxins I-III) with crab toxicity were isolated from the sea anemone Stichodactyla gigantea by gel filtration on Sephadex G-50 and reverse-phase HPLC on TSKgel ODS-120T and their complete amino acid sequences were determined. Gigantoxins II (44 residues) and III (48 residues) have LD(50) (against crabs) of 70 and 120 microg/kg, respectively, and are analogous to the known type 1 and 2 sea anemone sodium channel toxins, respectively. On the other hand, gigantoxin I (48 residues) is potently paralytic to crabs (ED(50) 215 microg/kg), although its lethality is very weak (LD(50)>1000 microg/kg). Interestingly, gigantoxin I has 31-33% homologies with mammalian epidermal growth factors (EGFs), with the same location of six cysteine residues. In accordance with the sequence similarity, gigantoxin I exhibits EGF activity as evidenced by rounding of A431 cells and tyrosine phosphorylation of the EGF receptor in the cells, although much less potently than human EGF. Gigantoxin I is the first example of EGF-like toxins of natural origin.     

A comparison of clinicopathological characteristics and long-term survival outcomes between symptomatic and screen-detected breast cancer in Japanese women

Background

Several studies from other countries have reported that patients with screen-detected breast cancer have better survival than those with symptomatic breast cancer. However, no such comparison has been performed in Japan. Therefore, we aimed to compare the clinicopathological characteristics and survival rates between symptomatic and screen-detected breast cancer in Japanese women.

Methods

From January 2000 to December 2004, 977 and 182 women with symptomatic or screen-detected breast cancer, respectively, underwent surgery at a single Japanese hospital. We retrospectively reviewed these patients’ clinicopathological data. Likelihood of death was estimated using the Kaplan–Meier method and the log-rank test. Multivariate analysis including mode of detection, tumor size, lymph node status, hormone receptor status, and adjuvant therapy administration was performed using the Cox proportional hazards model.

Results

Screen-detected breast cancer was associated with increased rate of breast-conserving surgery, non-invasive carcinoma, smaller tumor size, decreased lymph node involvement, increased hormone receptor positivity, and decreased adjuvant chemotherapy administration. Compared to women with symptomatic tumors, those with screen-detected tumors had improved overall and breast cancer-specific survival rates. Factors associated with survival in univariate analysis were screen detection, tumor size, lymph node status, progesterone receptor status, and adjuvant chemotherapy administration.

Conclusions

Breast cancer screening in Japanese women has led to increases in the rates of breast-conserving surgery, hormone receptor positivity, and survival rates along with reductions in axillary lymph node dissection and adjuvant chemotherapy administration.

     

Precancerous hepatic nodules had significant levels of telomerase activity determined by sensitive quantitation using a hybridization protection assay

BACKGROUND: Telomeric repeat amplification protocol using internal telomerase assay standard (ITAS) (conventional TRAP) has detected telomerase activity in various malignant tumors. With conventional TRAP, it is difficult to differentiate quantitatively low levels of telomerase activity between well-differentiated hepatocellular carcinomas (HCCs) and dysplastic nodules because of quantitative limitation. To apply a telomerase assay for differential diagnosis, we used a hybridization protection assay combined with TRAP (TRAP/HPA). This combination had better sensitivity and wider linearity than conventional TRAP. METHODS: TRAP/HPA was applied for quantitative measurement of telomerase activity in various hepatic tissues. Telomerase activity was evaluated in 10 precancerous hepatic nodules, 17 well-differentiated HCCs, 19 moderately differentiated HCCs, 5 poorly differentiated HCCs, 22 nontumorous chronic hepatic disease samples, and 2 normal liver tissues. RESULTS: Telomerase activity in HCCs tended to increase according to the malignant transformation. The average relative telomerase activity in 0.6 microg protein, which was expressed as cell equivalent activity of MKN-1, a gastric carcinoma cell line, was 8.5 in precancerous hepatic nodules, 87 in well-differentiated HCCs, 265 in moderately differentiated HCCs, 447 in poorly differentiated HCCs, and 0.4 in nontumorous hepatic tissues, including chronic liver diseases. CONCLUSIONS: TRAP/HPA was sensitive enough to distinguish the telomerase activity in precancerous hepatic nodules from that in other lesions. Telomerase activity in precancerous hepatic nodules was higher than that in nontumorous hepatic tissues. However, the activity in precancerous hepatic nodules was lower than that in well-differentiated HCCs, although statistically not significant. The authors suggest that precancerous hepatic nodules with telomerase activity above the diagnostic cutoff level (twice the highest activity in nontumorous hepatic tissues, or the 2 cell equivalent activity of MKN-1) should be treated as malignancy.