Monopolar and dipolar relaxation in spin ice Ho2Ti2O7.

Ferromagnetically interacting Ising spins on the pyrochlore lattice of corner-sharing tetrahedra form a highly degenerate manifold of low-energy states. A spin flip relative to this "spin-ice" manifold can fractionalize into two oppositely charged magnetic monopoles with effective Coulomb interactions. To understand this process, we have probed the low-temperature magnetic response of spin ice to time-varying magnetic fields through stroboscopic neutron scattering and SQUID magnetometry on a new class of ultrapure Ho2Ti2O7 crystals. Covering almost 10 decades of time scales with atomic-scale spatial resolution, the experiments resolve apparent discrepancies between prior measurements on more disordered crystals and reveal a thermal crossover between distinct relaxation processes. Magnetic relaxation at low temperatures is associated with monopole motion through the spin-ice vacuum, while at elevated temperatures, relaxation occurs through reorientation of increasingly spin-like monopolar bound states. Spin fractionalization is thus directly manifest in the relaxation dynamics of spin ice.

Spin-orbital short-range order on a honeycomb-based lattice.

Frustrated magnetic materials, in which local conditions for energy minimization are incompatible because of the lattice structure, can remain disordered to the lowest temperatures. Such is the case for Ba(3)CuSb(2)O(9), which is magnetically anisotropic at the atomic scale but curiously isotropic on mesoscopic length and time scales. We find that the frustration of Wannier's Ising model on the triangular lattice is imprinted in a nanostructured honeycomb lattice of Cu(2+) ions that resists a coherent static Jahn-Teller distortion. The resulting two-dimensional random-bond spin-1/2 system on the honeycomb lattice has a broad spectrum of spin-dimer-like excitations and low-energy spin degrees of freedom that retain overall hexagonal symmetry.

Antiferroquadrupolar ordering in a Pr-based superconductor PrIr(2)Zn(20).

An antiferroquadrupolar ordering at T(Q)=0.11 K has been found in a Pr-based superconductor PrIr(2)Zn(20). The measurements of specific heat and magnetization revealed the non-Kramers Γ(3) doublet ground state with the quadrupolar degrees of freedom. The specific heat exhibits a sharp peak at T(Q)=0.11 K. The increment of T(Q) in magnetic fields and the anisotropic B-T phase diagram are consistent with the antiferroquadrupolar ordered state below T(Q). The entropy release at T(Q) is only 20% of Rln2, suggesting that the quadrupolar fluctuations play a role in the formation of the superconducting pairs below T(c)=0.05 K.

Superconducting properties of the non-Fermi-liquid system beta-YbAlB4.

beta-YbAlB4 is the first Yb-based heavy fermion superconductor with Tc = 80 mK. Our study using high-purity single crystals reveals that strongly type-II heavy fermion superconductivity emerges from the non-Fermi-liquid state with enhanced ferromagnetic fluctuations. High sensitivity of Tc to sample purity indicates strong pair-breaking effects due to impurities, probably of nonmagnetic type, suggesting an unconventional character of the superconductivity.

Salivary excretion of N-nitrosodimethylamine in dogs.

Carcinogenic N-nitroso compounds (NOCs) are not only ingested from the environment but are also formed endogenously from precursors. It has been reported that nitrate, an NOC precursor, has an enterosalivary cycle and that the cycle increases the chance of exposure to NOCs. However, there is no information on the salivary excretion of NOCs. In the present study, the toxicokinetics of N-nitrosodimethylamine (NDMA) in dogs was evaluated, focusing on the salivary excretion. Following intravenous injection of 2 mg/kg NDMA, the plasma concentration showed a monoexponential decline, and the total body clearance and apparent distribution volume were greatly in excess of the hepatic plasma flow and total body water, respectively. A high concentration of NDMA was immediately detected in the plasma after oral administration of the same dose, and the oral bioavailability was almost 100%. NDMA was rapidly excreted into the saliva after both treatments, and the concentration in saliva was higher than that in the plasma. These results suggest that NDMA also has an enterosalivary cycle: NDMA is partially excreted from blood into saliva, delivered into the gastrointestinal tract by swallowing the saliva, and then completely reabsorbed into the systemic circulation. This concept was also supported by kinetic analysis based on a compartment model. The enterosalivary cycle of NDMA cannot be ignored in the risk assessment of carcinogenesis.

[A case of breast cancer with metastasis of multiple organs showing marked efficacy of medroxyprogesterone acetate (MPA)].

The patient, a 55-year-old female, was diagnosed as having right breast cancer (T1aN2M1, Stage IV) with metastasis of multiple organs (lung, pleura, bone, mediastinal and unilateral axillary lymph nodes) when she underwent tumorectomy. Postoperative adjuvant therapy was performed using oral administration of MPA (800 mg/day). After 3 months of this treatment, metastatic lesions in the lung and pleura had disappeared. After 37 months, complete remission (CR) was evaluated in the multiple lesions of bone metastasis. She achieved a complete remission (CR) by this treatment lymph nodes metastasis in both mediastinum after 24 months and unilateral axillae after 15 months. Complete response time was 38 months in both lung and pleura, 15 months in bone metastasis, 15 months in mediastinal lymph nodes, 24 months in unilateral ones. Normalization of tumor markers was acquired after 7 months of this hormonal therapy. This CR condition continues at present without severe complications.

Effect of hyperthermia on proliferation and deviation of carcinoembryonic antigen and squamous cell carcinoma-related antigen of human esophageal carcinoma cells in culture.

As a basic study of hyperthermia on malignant tumors, we investigated the kinetics of proliferative activity and the values of tumor markers carcinoembryonic antigen (CEA) and squamous cell carcinoma-related antigen (SCC) in a human esophageal carcinoma cell line, SGF-4, following a change of culture temperature. The temperature range allowing cultured SGF-4 cells to proliferate was from 37 degrees C to 40 degrees C. In an experiment examining the recovery of proliferative activity, no proliferative activity was observed after the cultured cells were exposed to 42 degrees C for 72 hours. The values of CEA and SCC as tumor markers were found to be increased in association with the cell damage due to the change of temperature. These markers could thus be useful as indicators for evaluations of hyperthermia therapy effectiveness.

Effect of endogenous hypergastrinemia on carcinogenesis in the rat esophagus.

We surgically prepared a hypergastrinemia model in rats and studied the effects of hypergastrinemia on chemically induced carcinogenesis in the esophagus. Operations were performed on 5-week-old male Donryu rats as follows: (1) truncal vagotomy plus pyloroplasty (group V), (2) segmental gastrectomy plus pyloroplasty (group G), (3) antrectomy (group A), and (4) no operation (group C) as a control. From the age of 6 weeks, the animals were given 0.003% N-methyl- N-amylnitrosamine (MAN) solution as drinking water for 8 weeks. After 20 weeks of MAN administration, the animals were bled and killed. The average serum gastrin levels in groups V and G were significantly higher than those groups C or A. There were significant differences between C and V in the incidence of carcinoma, and between V and A in the incidence of carcinoma including severe dysplasia. The incidence of histologically identified lesions per animal was determined, and significant differences were observed between C and both V and G in the incidence of carcinoma including severe dysplasia. Furthermore, we also detected gastrin receptors in the esophageal lesions produced by the oral administration of MAN to rats. The results of the present study suggest that endogenous hypergastrinemia has a positive influence on chemically induced carcinogenesis in the rat esophagus.

Laparotomy causes a transient induction of rat liver serine dehydratase mRNA.

Rat liver serine dehydratase mRNA shows rhythmicity with a high level at the onset of dark (19:00) and a low level at the onset of light (07:00). We have examined the effect of stress (laparotomy) on the rhythm. Upon laparotomy at 09:00 or 17:00, a marked induction of serine dehydratase mRNA occurred 2 h after operation. The elevated mRNA level then decreased and the original mRNA rhythm resumed 2 days later. By contrast, the transcription activator protein DBP mRNA level which shows a similar oscillation was not affected by this treatment. The induction was also seen in adrenalectomized rats that had been treated with hydrocortisone but not with saline or noradrenaline, indicating that glucocorticoids are absolutely necessary for the induction. Pretreatment of rats with phenoxybenzamine, and prazosin prevented the effect of laparotomy, but propranolol and yohimbine had no effect, indicating the necessity of the alpha 1-adrenergic stimulation for the induction. These results suggest that laparotomy releases glucocorticoids and neural noradrenaline that stimulates alpha 1-adrenergic receptors, thereby leading to the serine dehydratase gene expression.

[Successful treatment of advanced gastric cancer (Borrmann 1 type) with FTP chemotherapy after reduction surgery].

A 54-year-old man was diagnosed with Borr 1 type gastric cancer, located just below ECJ with some paraaortic lymph node metastase, during treatment of diabetes mellitus at another hospital. He underwent spleno-total gastrectomy for reduction. The metastatic lymph nodes of the para-aorta were not resected, so the surgery was considered palliative. We administered FTP chemotherapy (CDDP 110 mg/day 1, 5-FU 1,200 mg/day 1-5, THP-ADM 30 mg/day 1) 5 times following surgery. The metastatic lymph nodes were remarkably decreased in size by the initial treatment. The decrement was 52.4% after the initial treatment (PR). After the 4th treatment, there were no lymph nodes detected (CR). After the 5th treatment, CR continued. The PR period was considered to be 5 months, and that of CR 4 months. The patient has no renal or heart dysfunction, and no suppression of bone marrow. His quality of life is satisfactory, and he continues to work as prior to surgery. FTP chemotherapy is considered a successful regimen for postoperative chemotherapy.

TNF receptor number-dependent cytotoxicity to TNF-resistant human esophageal cancer cell lines by combination with recombinant human necrosis factor and hyperthermia.

The synergistic effect of recombinant human tumor necrosis factor (rh-TNF) and hyperthermia on five established cell lines of human esophageal cancer (SGF series) was analyzed by in vitro assays. The SGF cell lines were either resistant or slightly sensitive to rh-TNF. However, they became highly sensitive to rh-TNF even at as low a concentration as 10 U/ml and dose-dependently when combined with hyperthermia (43.5 degrees C, 60 min). This result was due to synergistic effects of rh-TNF and hyperthermia, and the degree of the effect increased with the hyperthermic temperature and TNF concentration. The number of TNF receptors per cell varied widely from cell line to cell line, from 4,400 to 23,100, which did not correlate to the extent of cytotoxicity by rh-TNF alone. The degree of synergistic effect of rh-TNF and hyperthermia was evaluated quantitatively in terms of a Synergistic Index (S. I. = Predicted cell viability/Experimental cell viability): A significant correlation was found between the logarithmic S. I. and the number of TNF receptors. These findings indicated that the combination of rh-TNF and hyperthermia produced a significant antitumor effect even on the cell lines poorly sensitive to TNF in a receptor-dependent manner, although the cellular sensitivity to TNF alone was not directly correlated to the number of TNF receptors.

[Clinicopathological evaluation of high-range hyperthermia for advanced thoracic esophageal carcinoma].

The effectiveness of high-range hyperthermia over 45 degrees C for advanced esophageal carcinoma was clinicopathologically evaluated. Fifty-eight patients with advanced thoracic esophageal carcinoma were treated with radio-chemotherapy. They were divided into two groups: group I included 32 cases, all of whom received hyperthermia (13 cases: high-range hyperthermia); group II included the other 26 cases. The patients were given 2 Gy/day for a total of 15 sessions in 3 weeks. Bleomycin and cisplatin in combination with 5-fluorouracil have been employed as chemotherapy. Hyperthermia was performed twice a week for a total of 6 sessions. Intraluminal heating was done using Japan Crescent Inc. IH-500 T (RF, 13.56 MHz), with an intraesophageal applicator and two extra-corporeal applicators on the chest and the back. Concerning local effects, the efficacy rate was 81.3% in group I (high-range: 92.9%), and 42.3% in group II. The histologic effectiveness, when Grade 2 and 3 are determined as histologically effective, were 64.3% (high range: 85.7%) and 50.0% in group I and II, respectively.

Prodrug activation via catalytic antibodies.

Prodrug activation via antibodies was examined by using the antibiotic chloramphenicol as a model drug. Based on the conformational change between substrate and product, this antibody-catalyzed reaction was designed to prevent product inhibition, thus enhancing turnover. Antibodies elicited against a phosphonate transition-state analogue were found to catalyze hydrolysis of a nonbioactive chloramphenicol monoester as a prodrug at a significantly higher rate above the uncatalyzed background reaction to regenerate chloramphenicol as a parent molecule. The antibody-catalyzed prodrug activation was tested by the paper-disc diffusion method using Bacillus subtilis as an indicator strain. The antibody 6D9 catalyzes the reaction with multiple turnover to generate enough chloramphenicol to inhibit bacterial growth, as indicated by a clear inhibitory zone after incubation with monoester. Using the same method, no inhibition was detected by incubation of either the monoester or the antibody alone. This result reveals that only the antibody hydrolytically activates the monoester, which can be expected to be a suitable prodrug, as it is resistant to the action of bacterial hydrolytic enzymes. The approach in this study demonstrates the use of catalytic antibody technology in medicine and may be applicable to drugs with undesirable effects, particularly in the field of cancer therapy.

Role of the basic amino acid cluster and Glu-23 in pyrimidine dimer glycosylase activity of T4 endonuclease V.

T4 endonuclease V [endodeoxyribonuclease (pyrimidine dimer); deoxyribonuclease (pyrimidine dimer), EC 3.1.25.1] initiates repair of damaged DNA by hydrolysis of the N-glycosyl bond at the 5' side of a pyrimidine photodimer in double-stranded DNA. To study one of the active sites of T4 endonuclease V, systematic site-directed mutagenesis was performed on the synthetic T4 endonuclease V gene, in parallel with three-dimensional structure analysis by x-ray crystallography. The mutant proteins were evaluated for DNA glycosylase activity using an oligonucleotide duplex (14-mer) containing a single thymidine dimer as a substrate. Replacement of either Glu-23 with glutamine or asparatic acid or Arg-3 with glutamine completely abolished DNA glycosylase activity. Mutation of Arg-3 to lysine or of Arg-26 to glutamine or lysine in a basic amino acid cluster caused serious defects in DNA glycosylase activity, which are reflected in the increases in Km and decreases in kcat of DNA glycosylase activity. On the other hand, substitutions of lysine for Arg-22 or of glutamine for Arg-117 or Lys-121 resulted in increases in the Km value. The completely inactive mutant proteins, E23Q and R3Q, in which glutamine was substituted for Glu-23 and Arg-3, respectively, were further investigated by CD spectroscopy for their ability to bind the oligonucleotide substrate. It was found that the E23Q protein retained specific substrate-binding ability, whereas the R3Q protein did not. These results indicate that Glu-23 plays an important role in catalysis of the DNA glycosylase reaction, and that Arg-3 is a crucial residue for substrate binding. In addition, Arg-22, Arg-26, Arg-117, and Lys-121 in the basic amino acid cluster also participate in substrate binding. We conclude that the basic amino acid cluster in T4 endonuclease V is an essential structure for DNA glycosylase activity.

Participation of glutamic acid 23 of T4 endonuclease V in the beta-elimination reaction of an abasic site in a synthetic duplex DNA.

T4 endonuclease V catalyzes the hydrolysis of the glycosyl bond of a thymine dimer in a DNA duplex and the cleavage of the 3'-phosphate by beta-elimination. We have previously identified a catalytic site for the first reaction (pyrimidine dimer-glycosylase activity) by systematic mutagenesis (Doi et al. Proc. Natl. Acad. Sci. USA 1992 in press) and by x-ray crystallography (Morikawa et al. Science, 256: 523-526, 1992). The results showed that replacement of Glu23 with either glutamine or aspartic acid completely abolished the glycosylase activity. We describe the investigation of the second reaction (apurinic/apyrimidinic endonuclease activity), using twenty two mutants of T4 endonuclease V plus a DNA mini duplex containing an abasic site. Replacement of Glu23 by glutamine abolished the second reaction, but replacement with aspartic acid did not. The pH optima of the mutant (23 Asp) and the wild type were found to be 5.0 and 5.5, respectively. We conclude that the carboxylate anion in position 23 may act as a general base in the beta-elimination reaction of the endonuclease.

Surgical treatment of carcinoma of the esophagogastric junction.

Forty-seven patients with carcinomas of the esophagogastric junction were operated. In acquiring complete dissection of lymph nodes located at the splenic hilus and along the splenic artery, splenectomy with or without caudal hemipancreatectomy was performed in 29 of 47 patients. To avoid leaving carcinoma cells behind in the remaining esophagus margin of resection, 20 patients underwent left thoracophrenicolaparotomy and 14 patients received blunt dissection of the intrathoracic esophagus. Five-year survival of 55.6% was observed in curative groups of the present study. No operative mortality was present.

Appearance of a carcinoid-like pattern in rat hepatic tumors induced by 3'-methyl-4-dimethyl-aminoazobenzene.

This study investigated the histological distribution of argyrophilic cells in experimental hepatic neoplasms, the number of these cells, and the proportion of neoplasms with such cells. Seventy 6-week-old male Donryu rats were given a 0.06% 3'-methyl-4-dimethyl-aminoazobenzene (3'-MeDAB) diet for 10 weeks, followed by an ordinary diet for an additional 10 weeks. Of the 70 rats, 50 were used for this investigation; 29 had hepatic tumors, 18 had cholangiofibrosis, and the other three had oval cell proliferation only. Hepatic tissues were stained with Grimelius and Fontana-Masson stains as well as routine hematoxylin-eosin stain. Argyrophilic cells were found in the hepatic neoplasms of 8 rats without argentaffin cells, while cholangiofibrosis was associated with argentaffin cells in almost all cases. Of the 8 rats with argyrophilic cells, three had an abundant population of these cells. The argyrophilic cells were found in areas of the neoplasms with a glandular, trabecular, tubular, or poorly differentiated pattern. Electron microscopy revealed that the neoplastic cells with a positive argyrophil reaction contained small round electron-dense endocrine granules. In addition, in the areas of cholangiofibrosis, two different types of gut endocrine cells were present (G and EC cells). These results suggest that 3'-MeDAB might induce hepatic carcinoid under certain conditions, though we have yet to confirm the development of a pure hepatic carcinoid due to this substance.

[A giant struma histologically confirmed as a medullary carcinoma with multiple systemic bone metastasis].

Reported is the case of a 46 year old woman with no significant family medical history, who presented a neck tumor that she had had for about ten years. This large tumor was noted on her admittance to hospital due to a bone fracture. She subsequently underwent a resection of this giant neck tumor. A histologic examination of the specimen revealed a medullary carcinoma of the follicular variety. Silver impregnation by the Grimelius method caused a positive reaction, and an electron-microscopic examination revealed round, electron-dense, endocrine granules about 195 nm in diameter, Immunohistochemically, the carcinoembryonic antigen (CEA) and the presence of calcitonin proved the cells to be cancerous.