Functional studies on the anti-pathoangiogenic properties of CM101.

Group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress produces a polysaccharide exotoxin (CM101) which has been previously described as GBS toxin. CM101 infused i.v. into tumor-bearing mice causes rapid tumor neovascularitis, infiltration of inflammatory cells, inhibition of tumor growth and tumor apoptosis. CM101 has successfully completed phase I studies in refractory cancer patients with very encouraging results. We have now demonstrated a mechanism of action for CM101. Using a normal mouse tumor model, we have examined tumor and normal tissues which were harvested at 0, 5, 15, 30 and 60min post-infusion of either CM101 or dextran. We present evidence that CM101 is rapidly (within the first 5min) bound to the tumor neovasculature. Complement is activated by the alternative pathway (C3) and leukocytes start to infiltrate the tumor within the first 5min. Through RT-PCR and immunohistochemical techniques, we demonstrate that proinflammatory cytokines, interleukin-6 and tumor necrosis factor (TNF)-alpha, are up-regulated in infiltrating leukocytes and TNF receptor 2 is up- regulated in the targeted tumor neovasculature. Combined, these events constitute possible explanations for the observed pathophysiology of tumor ablation.

Transcutaneous electrical acupoint-stimulation potentiates the anesthetic effect of enflurane in humans.

The effect of transcutaneous electrical acupoint stimulation (TEAS) on enflurane anesthesia and hemodynamic changes during craniotomy was studied. Eighty neurosurgical patients were randomly divided into two groups. Anesthesia was induced with fentanyl, droperidol, thiopental, and suxamethonium by intubation. In group A, anesthesia was maintained with enflurane (n=40), and in group B was supplemented by TEAS with Han's acupoint nerve stimulator (HANS) to Hegu, Yuyao, and Fengchi points on the operated side (n=40). The results showed that the ratio between expired concentration and minimum alveolar concentration of enflurane during operation in group B was 37.8%-47% lower than that in group A, and that the hemodynamics were more stable during operation. The results also demonstrated that the patients in Group B recovered faster after operation. It was concluded that TEAS with HANS significantly potentiated the anesthetic effect of enflurane.

[A study on combined acupuncture and enflurane anesthesia for craniotomy].

The reinforcing effect of transcutaneous acupoint electric stimulation (TAES) with enflurane anesthesia during craniotomy was studied. 110 neurosurgical patients were randomly divided into three groups. Anesthesia was maintained with enflurane in group A (n = 40); in group B, enflurane anesthesia was supplemented by TAES with Han's acupoint nerve stimulator (HANS) at Hegu, Yuyao and Fengchi points on the operated side (n = 40); in group C, enflurane anesthesia was supplemented by TAES and scalp infiltration with 0.5% procaine (n = 30). The results showed that the minimum alveolar concentration (MAC) of enflurane in group B and C decreased 37.8-47.0% and 42.1-66.1% respectively than that in group A. The hemodynamics was more stable during operation, and the patients recovered faster after operation in group B and C. It was concluded that TAES with HANS significantly potentiated the anesthetic effect and decreased the side effects of enflurane during operation, and that the triple combination of TAES, enflurane and scalp infiltration with procaine proved to be a better anesthetic method for craniotomy.

Isolation of a mitomycin-resistant human lung adenocarcinoma cell subline to investigate the modulation by sodium butyrate of cell growth and drug resistance.

We developed a mitomycin C (MMC)-resistant human lung adenocarcinoma cell subline, SPC-A1/DM4, from cloned SPC-A1/D13 parent cells by 1 h exposures to escalating concentrations of the drug over 17 months. A 5.9-fold resistance to MMC and a 3.8-fold cross-resistance to cisplatin were present in resistant cells compared with parent cells. This phenotype was stable in the absence of drug exposure for at least 6 months. Sodium butyrate (NaBu), a widely used differentiating agent, was shown to inhibit cell proliferation in a dose-dependent manner, with the cytostatic concentration of 2 mM. This NaBu-induced growth inhibition was reversible. However, SPC-A1/DM4 cells, after recovery from the cytostasis induced by 2 days treatment with 2 mM NaBu, became 2-fold more sensitive to MMC than the cells not exposed to the agent. Meanwhile, the cisplatin response of these treated cells reached a level comparable to the parent cells. This modulation by NaBu of drug resistance could be retained for at least 1 month. Treatment with 2 mM NaBu for 2 days caused inhibition of DNA synthesis and accumulation of cells in the G1 and G2/M-phases of the cell cycle. Correlated with these were a marked increase of protein content in these cell subpopulations and an enhanced RNA synthesis. In addition, NaBu-treated cells acquired development of endoplasmic reticulum and accumulated lipid droplets. These morphological alterations were accompanied by a significant decrease in the ratio of nuclear to cytoplasmic areas. These findings suggest that NaBu is potentially useful in the treatment of drug-resistant non-small cell lung cancer. Information about the NaBu-induced phenotypic alterations may offer a clue to the understanding of its long-term effect on drug resistance.

A self-induced translation model of myosin head motion along thin filament in muscle contraction.

Evidence has been accumulating that muscle contraction may not be associated with the power stroke of the cross-bridges tightly coupled with ATP hydrolysis cycle. We have constructed a new contraction model which includes a number of basic properties of contraction processes not taken into consideration in the models hitherto reported. The basic assumption is that, when one head of a myosin molecule attaches to an actin monomer on thin filament, conformational changes take place in the neighbouring actin monomers to result in their non-symmetrical charge distribution to exert electrostatic force on the unattached head of the same myosin molecule in one direction. Thus, the unattached head moves along thin filament to attach to another actin monomer, while the already attached head detaches from thin filament. These steps are repeated to cause muscle contraction. The above contraction model can explain the results of our X-ray diffraction experiments as well as the results reported by other authors.

Establishment and characterization of human malignant pleural mesothelioma cell line SMC-1.

A cell line (SMC-1) has been established from the resected tissue of a patient with malignant pleural mesothelioma which has been pathologically confirmed to be the mixed type. The cell line is characterized by the pleomorphy and multilayered growth of the cells with the population-doubling time of approximately 32 h, the highest mitotic index of 46--50% and the modal chromosome number of 69-70. Transplantation of the cells into the animals can produce tumors bearing histological resemblance to the original material. The cultured cells, xenografted tumor cells and the cells from the host specimen show similar histochemical expressions. These data meet the requirements of a human malignant pleural mesothelioma cell line. The establishment of this cell line will serve as a useful tool in clinical research of diagnosis and treatment of this devastating disease.