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Biomedical subjects

N Hara

Publications and source records attributed to N Hara.

At least 325 records · Page 18Linked to original sources

[Neoadjuvant therapy of stage III non-small cell lung cancer].

Locally advanced stage III disease constitutes 30 to 40% of the entire group of non-small cell lung cancer. Surgery is the only curable modality in this stage disease, but resection rate is less than 40%. Even in completely resected patients 5-year survival is only 30%. Several reports have evaluated postoperative chemotherapy and radiotherapy. Prospective randomized studies, however, have failed to demonstrate a survival advantage from adjuvant therapy. Neoadjuvant therapy is under investigation in attempt to improve survival of stage III patients. Preliminary data show that neoadjuvant therapy could increase resection rate and improve survival with moderate toxicities. However, there are many problems in study design such as the use of single-arm studies with short duration of follow-up, lack of accurate staging of selected patients and no precise definitions of resectability for stage III disease. Therefore, there is an urgent need for well designed randomized trial to confirm whether neoadjuvant therapy offers a survival advantage on locally advanced stage III disease.

Antineoplastic Combined Chemotherapy Protocols↗

[An early phase II study of CPT-11 in primary lung cancer].

An early phase II study of CPT-11 was carried out in patients with primary lung cancer in 15 institutions throughout Japan. The efficacy and safety of CPT-11 were studied at 200 mg/m2 based on the results of the previous phase I study. Thirty-eight of 52 enrolled patients were eligible. CPT-11 proved to be effective for primary lung cancer. The response rates were 20.0% (7/35) for non-small cell lung carcinoma and 33.3% (1/3 for small cell lung carcinoma. Hematological toxicities included leukopenia (less than or equal to 3,000) in 44.7% of the patients. Other major toxicities were nausea/vomiting (greater than or equal to grade 2) in 50.0% and diarrhea (greater than or equal to grade 2) in 47.4%.

Adenocarcinoma↗

Enhanced leukotriene C4 synthase activity in thioglycollate-elicited peritoneal macrophages.

The utilization of LTA4 by peritoneal macrophages (MO) obtained from untreated rats (control) as well as by those elicited from rats was investigated at designated intervals (on days 3, 7, and 14) following the intraperitoneal injection of thioglycollate (TG). On day 7 following the injection the elicited MO converted LTA4 to LTC4 at the highest rate while the resident MO showed the lowest rate. The conversion of LTA4 to LTC4 and LTB4 was next examined by using each MO lysate. The apparent LTC4 synthase activity was significantly higher in the MO lysate both on day 3 and day 7, with the latter being the highest value obtained. The GSH S-transferase activity in each lysate using as the substrate, DNCB was significantly lower on day 3 but significantly higher on day 7 as compared to control values. However, this elevated activity was less variable than that observed with LTC4 synthase. The possible implication for these observations is discussed.

Animals↗

Influence of chemotherapeutic agents on superoxide anion production by human polymorphonuclear leukocytes.

The effects of 11 chemotherapeutic agents on superoxide anion (O2-) production were examined in human polymorphonuclear leukocytes (PMNL). All drugs, except predonine, were found to suppress O2- production in PMNL. Adriamycin (doxorubicin), mitomycin C, vindesine, cisplatin, etoposide, nimustine, and pepleomycin suppressed O2- production at relatively low drug concentrations, whereas methotrexate, 5-fluorouracil and vincristine suppressed O2- production at high drug concentrations. Time-dependent suppression of O2- production was evaluated in four drugs, namely Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cisplatin, vindesine, and methotrexate. Only Adriamycin showed suppressive effect on PMNL-derived O2- production in a time-dependent manner. Production of O2- by PMNL is a fundamental element for its bactericidal activity. The authors' results showed suppression of O2- production in PMNL in the presence of chemotherapeutic agents. This indicates a relationship between chemotherapy drugs and susceptibility to infection. The influence of chemotherapeutic agents on O2- production by PMNL should thus be taken into consideration when assessing defense mechanisms and susceptibility to infection of patients treated with these drugs.

Anions↗

Extracellular tumor necrosis factor induces a decreased K+ conductance in an identified neuron of Aplysia kurodai.

Recombinant human tumor necrosis factor (rhTNF) was pressure-applied onto the the soma of identified neuron R12 in the Aplysia abdominal ganglion. rhTNF induced a slow inward current (ITNF, 80-100 s in duration, 5-10 nA in amplitude) associated with a conductance decrease. ITNF begins 1-2 s after applying rhTNF and peaks in 5-6 s. ITNF was decreased by hyperpolarization and had a reversal potential of approximately -87 mV (close to the K+ equilibrium potential). Ion substitution and pharmacological experiments suggest that ITNF is due to a decreased K+ conductance and that TNF, a product of macrophages, may form an important link in communications between nervous and immune systems.

Animals↗

Activation of single Ca2(+)-dependent K+ channel by external ATP in mouse macrophages.

Single Ca2(+)-dependent K+ currents responding to external ATP were recorded from cell-attached patches on mouse peritoneal macrophages. Extracellularly applied ATP activated an inward single-channel current with a conductance of 25 pS and a reversal potential of -79 mV (pipette potential, Vp) when the pipette contained a 145 mM KCl solution. The reversal potential was shifted 56 mV positive by a 10-fold reduction in external (pipette) K+ concentration. The effect of ATP was abolished by either removal of external Ca2+ or treatment with an intracellular Ca2+ chelator, the acetoxymethyl ester of 1,2-bis (2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid (BAPTA-AM). This channel has a mean open time of 9.1 ms and open probability was not strongly dependent on Vp in the range tested (+120 to -30 mV).

Adenosine Triphosphate↗

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat.

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.

Animals↗

Novel vitamin D3 derivatives, 26-homo-delta 22-dehydro-1 alpha,25(S)-dihydroxyvitamin D3 and 26-homo-delta 22-dehydro-1 alpha,25(R)-dihydroxyvitamin D3: preferential activity in c-myc mRNA production and in induction of phenotypic differentiation of HL-60 cells.

Novel vitamin D3 derivatives, 26-homo-delta 22-1 alpha,25(S)-dihydroxyvitamin D3 and 26-homo-delta 22-1 alpha,25(R)-dihydroxyvitamin D3 were compared with the native hormone, 1,25-dihydroxyvitamin D3, and with other vitamin D3 derivatives, in inhibition of cell growth, induction of phenotypic differentiation, and c-myc mRNA reduction of HL-60 cells. The degree of inhibition in cell growth caused by 26-homo-delta 22-1 alpha,25(S)-(OH)2D3 was the greatest followed by 26-homo-delta 22-1 alpha,25(R)-(OH)2D3. The ability to reduce NBT was parallel to that to inhibit cellular proliferation. 26-homo-delta 22-1 alpha,25(S)-(OH)2D3, 26-homo-delta 22-1 alpha,25(R)-(OH)2D3, 24-homo-24-F2-1 alpha,25-(OH)2D3, and 1 alpha,24(R)-(OH)2-26-Cl-D3 were more active than 1 alpha,25-(OH)2D3 in the induction of OK-M1+ and OK-Mo-2+ HL-60 cells. Using two color flow cytometric analysis, the percentages of OK-M5(+)- and OK-DR(+)-HL-60 cells were 33% in the treatment with 26-homo-delta 22-1 alpha,25(S)-(OH)2D3 plus interferon-gamma (IFN-gamma) but 14% in the treatment with 1 alpha,25-(OH)2D3 plus IFN-gamma. 26-Homo-delta 22-1 alpha,25(S)-(OH)2D3 has an inhibitory effect on c-myc reduction in treated HL-60 cells. These results suggest that the novel vitamin D3 derivatives, 26-homo-delta 22-1 alpha,25(S)-(OH)2D3 and 26-homo-delta 22-1 alpha,25(R)-(OH)2D3, have preferential activity in inducing phenotypic differentiation and in inducing cell proliferation related c-myc mRNA activity.

Calcitriol↗

Glucose infusion abolishes the excessive ATP degradation in working muscles of a patient with McArdle's disease.

A 23-year-old woman with McArdle's disease performed mild leg exercise on a bicycle ergometer. Saline or 10% glucose solution was infused throughout exercise. After exercise with saline infusion, her plasma concentrations of ammonia, hypoxanthine and creatine kinase increased greatly. Conversely, after exercise with glucose infusion, there were no appreciable changes in these plasma substances. In addition, she noticed that glucose infusion relieved her from muscle symptoms during exercise. These findings suggest that glucose infusion to patients with McArdle's disease ameliorates excessive ATP degradation in exercising muscles.

Adenosine Triphosphate↗

The benefit of cisplatin-based polychemotherapy for adenocarcinoma of the lung. The Kyushu Lung Cancer Chemotherapy Study Group.

We studied the efficacy of cisplatin-based polychemotherapy for adenocarcinoma of the lung. A total of 136 patients were randomized for treatment with either cyclophosphamide, Adriamycin, cisplatin and mitomycin C (CAPM) or mitomycin C, cytosine arabinoside and tegafur (MCT). Radiation was given to the chests of patients at stage III. The differences in the response rate (35% in the CAPM arm and 13% in the MCT arm) were statistically significant (P less than 0.01). However, the significant difference was observed in stage-IV patients (CAPM, 33%; MCT, 4%; P less than 0.001) and not in stage-III patients (CAPM, 40%; MCT, 40%). The median period of survival was 9.5 months for the CAPM arm and 5.5 months for the MCT arm (P less than 0.035, Wilcoxon-Gehan test; P less than 0.1, log-rank test). Improved median survival for the CAPM regimen was demonstrated only by stage-IV patients (CAPM, 10 months; MCT, 5.5 months; P less than 0.025, Wilcoxon-Gehan test; P less than 0.05, log-rank test). The duration of the response, including PRs and NCs, was significantly different depending on the treatment, showing 5 months for the CAPM arm and 3 months for the MCT arm (P less than 0.05). The significant difference was also only observed in stage-IV patients. Myelosuppression was more severe with CAPM than with the MCT regimen. Nausea and vomiting were significantly increased in patients receiving the CAPM regimen. However, all toxicities were acceptable and there were no treatment-related deaths. We concluded that cisplatin-based chemotherapy, CAPM therapy, was of more benefit to patients with adenocarcinoma of the lung than MCT therapy.

Adenocarcinoma↗

Synthesis and biological activity of (22E,25R)- and (22,25S)-22-dehydro- 1 alpha,25-dihydroxy-26-methylvitamin D3.

Both 25-epimers of (22E)-22-dehydro-1 alpha,25-dihydroxy-26-methylvitamin D3 [22-dehydro-26-methyl-1,25-(OH)2D3] were synthesized. The biological activity of these compounds was tested in binding affinity to chick intestinal receptor protein of 1 alpha,25-dihydroxy-vitamin D3 [1,25-(OH)2D3] and in stimulating for intestinal calcium transport and bone calcium mobilization with vitamin D-deficient rats. The relative potency of (25R)- and (25S)-22-dehydro-26-homo-1,25-(OH)2D3 and 1,25-(OH)2D3 in competing for the intestinal cytosolic binding was 1.7:1.5:1. A similar order of activity was observed on intestinal calcium transport and bone calcium mobilization. In the ability for stimulation of intestinal calcium transport, (25R)- and (25S)-22-dehydro-26-methyl-1,25-(OH)2D3 were about 3.6 and 2.1 times as active as 1,25-(OH)2D3, respectively. In bone calcium mobilization tests, (25R)- and (25S)-22-dehydro-26-methyl-1,25-(OH)2D3 were estimated to be 2.2 and 1.6 times as potent as 1,25-(OH)2D3, respectively.

Animals↗

Acid secretagogue mechanisms of a GABA-mimetic (PCPGABA) in the anesthetized rat: effects of hypothermia.

The secretagogue action of lipophilic, GABA-mimetic, beta-(p-chlorophenyl)-gamma-aminobutyric acid (PCPGABA) was studied in the rat in relation to body temperature. PCPGABA (2 to 8 mg/kg s.c.) stimulated acid output in the urethane-anesthetized rat whose core temperature ranged between 28 to 30 degrees C. However, this stimulatory effect of PCPGABA totally disappeared in the same animal whose rectal temperature was maintained at the normal unanesthetized level (37-39 degrees C), whereas the acid secretory responses to histamine and bethanechol were not modified with the change in the thermoregulation. This suggests that the thermoregulation mechanisms are implicated in acid secretagogue action of centrally acting gastric stimulants.

Animals↗

Extracellular ATP activates Ca2(+)-dependent K+ conductance via Ca2+ influx in mouse macrophages.

1. Using the perforated patch recording, the effects of ATP on membrane current were investigated in mouse peritoneal macrophages. 2. Extracellularly applied ATP induced a biphasic current consisting of a initial inward current [Ii(ATP)] followed by an outward current [Io(ATP)]. These currents were associated with a marked increase in conductance at their peaks. 3. Ii(ATP) reversed close to 0 mV and was attenuated by removal of external Na+. 4. Io(ATP) reversed near -80 mV and was increased by decreasing the external concentration of K+. 5. Io(ATP) was completely abolished by removal of external Ca2+, treatment with an intracellular Ca2+ chelator, the acetoxymethyl ester of 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetra acetic acid (BAPTA-AM) and bath applied quinidine but not tetraethylammonium (TEA) or apamin. 6. These results suggest that Ii(ATP) and Io(ATP) are due to an activation of nonspecific cationic and Ca2(+)-dependent K+ conductances, respectively, and raise the possibility that the putative ATP receptor may be important in regulating macrophage functions, motility, phagocytosis and cytokines secretion.

Adenosine Triphosphate↗

Large cell carcinoma of the lung. Prognostic implications of histopathologic and immunohistochemical subtyping.

Fifty-four patients with large cell carcinoma of the lung were treated surgically, and the prognostic factors were examined histologically and immunohistochemically. Based on evidence of intercellular cohesion, as seen in the histologic results, the patients were placed into two subtypes, compact growth type and louse structure type. The survival rates were 46% and 28% at five years, respectively (P less than 0.05). Immunohistochemically, keratin, epithelial membrane antigen (EMA), secretory component, lactoferrin, and carcinoembryonic antigen (CEA), as histologic markers of epithelial differentiation, were detectable in large cell carcinoma of both types and more frequently in the compact growth type than in the loose structure type. The difference was significant in case of detection of keratin, EMA, and CEA (P less than 0.05). These observations suggest that a large cell carcinoma may differentiate into an adenocarcinoma or squamous cell carcinoma. The presence of intercellular cohesion and use of these markers reflect prognosis of the disease.

Adult↗

Recombinant granulocyte colony-stimulating factor and lipopolysaccharide maintain the phenotype of and superoxide anion generation by neutrophils.

Superoxide anion (O2-) generation by human blood neutrophils induced by phorbol myristate acetate, formyl-methionyl-leucyl-phenylalanine, and monoclonal antibody YI51 was measured 24 h after incubation in medium alone, medium with recombinant human granulocyte colony-stimulating factor (rG-CSF), and medium with lipopolysaccharide (LPS). Monoclonal antibody YI51 was able to bind to neutrophils and induce O2- generation after the addition of anti-mouse immunoglobulin antibody as a cross-linking agent. In the 24-h culture, there was no significant difference in neutrophil survival among the three cultures. The amount of O2- generated by neutrophils in control medium markedly decreased compared with that before culture. However, cells in medium with rG-CSF or LPS maintained the ability to generate O2- well or moderately, respectively. Thus, the activity maintained by rG-CSF and LPS was neutralized by the anti-G-CSF serum. Furthermore, significant amounts of G-CSF were detected in supernatants of neutrophils cultured with LPS for 24 h. It was not detectable, however, in control supernatants. To examine whether the phenotype of the plasma membrane of cells changed in the 24-h culture, expression of CD16 (FcR III) and YI51 antigens was analyzed by flow cytometry. The expression of CD16 and YI51 antigens on cells cultured with rG-CSF or LPS was maintained compared with that of control cells. These observations thus indicate that G-CSF is one of the factors essential to maintain the functioning and phenotype of mature neutrophils.

Antigens, CD↗

An epidemiological study of the influence of sweets intake and toothbrushing on dental caries among children in Japan.

The study was designed to determine the influence of confectionery and beverages intake and of toothbrushing on infant dental caries. The participants were 700 three year old Japanese children from an urban area near Tokyo. The prevalence of caries in those who frequently consumed confectionery and beverages was higher than the prevalence in those who did not take them. However, the prevalence in children with a habit of toothbrushing did not differ from that of those without the habit. This study shows that restricting consumption of confectionery and beverages may be effective in preventing dental caries; however, encouragement of toothbrushing may not be effective in limiting dental caries progression.

Beverages↗

[Ulcerogenic effect of a GABA derivative, baclofen, in the rat: effect of hypothermia].

The ulcerogenic action of baclofen, a lipophilic derivative of GABA, was studied in the urethane anesthetized rat in relation to body temperature. Baclofen at the doses of 2, 4 and 8 mg/kg, s.c. induced gastric ulceration in a dose-dependent manner in the hypothermic (body temperature: 28-30 degrees C) rat. Duodenal ulcers were also observed in about 80% of the hypothermic animals treated with the highest dose of baclofen. Baclofen, even at 8 mg/kg, s.c., however, failed to induce gastric ulceration in the normothermic (body temperature: 37-38 degrees C) rat. Histamine, at the secretagogue dose causing acid secretion as potently as 8 mg/kg of baclofen, induced gastric ulcers in both the hypothermic and the normothermic rats. These results indicate that the ulcerogenic effect of baclofen is closely related to the thermoregulation mechanism and may provide important clues for clarifying the pathophysiology of gastroduodenal ulcers induced by hypothermic treatments such as water-immersion stress ulcers or cold exposure ulcers.

Animals↗

Effects of GABA antagonists and structural GABA analogues on baclofen stimulated gastric acid secretion in the rat.

The effects of GABA receptor antagonists (bicuculline and phaclofen) and structural GABA-analogues on baclofen stimulated gastric acid secretion were studied in standardized perfused rat stomach preparations. Pretreatment with bicuculline, a GABAA-receptor antagonist, in the doses of 1 and 3 mg/kg, subcutaneously, had no influence on the gastric acid response to baclofen. In addition, phaclofen, a GABAB antagonist, in the doses of 3 to 30 mg/kg, intravenously, was found to have no significant effect on the acid response to baclofen. However, GABA-analogues (MOPS and ABA; 10-30 mg/kg, i.v.) and lipophilic GABA derivatives structurally related to beta-amino acids (APPA and APHA; 30 mg/kg, i.v.) significantly counteracted the secretagogue action of baclofen. Further experiments on APPA action showed that the antisecretory effect of APPA could be overcome by higher doses of baclofen. APPA did not affect bethanechol stimulated acid secretion. These results suggest that the secretagogue action of baclofen is independent to GABAA- and GABAB-receptors and that APPA may interact with baclofen in regulation mechanisms of acid secretion, although further investigations are necessary to define the mode of action of APPA on the GABA-ergic system.

Amino Acids↗