Inhibition of Autophagy by 3-MA Enhances the Effect of 5-FU-Induced Apoptosis in Colon Cancer Cells

Background  5-fluorouracil-(5-FU)-based adjuvant chemotherapy is widely used for the treatment of colorectal cancer. However, 5-FU resistance in the course of treatment has become more common. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Methods  Two colon-cancer-derived cell lines, colon26 and HT29, were used to investigate the effect of 5-FU, 3-methyladenine (3-MA, an autophagy inhibitor), or their combination on apoptotic cell death and autophagy. MTT assay, Hochest plus propidium iodide (PI) staining, and DNA fragmentation assay were used to observe apoptosis. Meanwhile, monodansylcadaverine (MDC) was used to detect autophagy. Finally, immunoblotting assay was used to explore the molecular change that occurred. Results  We observed the apoptosis induced by 5-FU in colon cancer cells. Meanwhile, autophagy was also stimulated. The combination treatment of 3-MA and 5-FU significantly increased the apoptotic cell death. By isolating the subcellular fractions of mitochondria and cytosol, we observed that the release of cytochrome c was increased in combination-treated cells. Cytochrome c resulted in the activation of caspase-3, thus activating PARP. Moreover, the anti-apoptotic protein, Bcl-xL, was significantly downregulated by 3-MA. Conclusions  Our results suggest that 5-FU-induced apoptosis in colon cancer cells can be enhanced by the inhibitor of autophagy, 3-MA. Autophagy might play a role as a self-defense mechanism in 5-FU-treated colon cancer cells, and its inhibition could be a promising strategy for the adjuvant chemotherapy of colon cancer.     

Reaction time to peripheral visual stimuli during exercise under normoxia and hyperoxia

The purpose of this study was to test if increased oxygen availability affected simple reaction time (RT) to peripheral visual stimuli during exercise. Twelve male participants performed RT tasks at rest, during cycling with three different workloads (100, 150, and 200 W), and after exercise. We fractionated RT into Premotor time and Motor time. Under normoxia, Premotor time significantly increased during exercise at 200 W (mean ± SD, 224.7 ± 34.8 ms) relative to that at rest (213.3 ± 34.1 ms) (P < 0.05). In contrast, we found no difference in Premotor time between at rest (214.0 ± 27.0 ms) and at 200 W (213.0 ± 21.6 ms) under hyperoxia. Furthermore, Premotor time significantly decreased at 150 W (201.3 ± 22.4 ms) relative to that at rest under hyperoxia (P < 0.05). These results suggest that increased oxygen availability during exercise has beneficial effects on perceptual performance.     

Supplementary Thyroxine Therapy in Patients with Hypothyroidism Induced by Long-Term Anticonvulsant Therapy

Of 287 patients under long-term therapy with anticonvulsants, 24 with low serum thyroxine and free thyroxine concentrations were prescribed supplementary thyroxine in the present study. In addition, the basal metabolic rate (BMR) was measured in 13 out of 24 patients and in eight of them it was low (under -15%). Serum thyroid hormone concentrations improved after administration of thyroxine. However, improvement of the BMR was not obtained after one month of supplementary therapy. EEG after administration showed an increase in the power spectra of the occipital alpha 2 band (10.0–12.8 Hz) and beta 1 band (13.0–19.8 Hz), and a decrease in that of the theta band (4.0–7.8 Hz). The inter-peak latency from wave I to wave V in the ABR was normalized after administration, These results suggest that supplementary therapy with thyroxine may be necessary in patients with hypothyroidism induced by anticonvulsants.     

Proton Beam Therapy for Patients with Esophageal Carcinoma

Fifteen patients with esophageal carcinoma (superficial, sixcases; advanced, nine cases) were treated with 250 MeV protonbeam irradiation with or without external x-ray irradiation(12 MV linear accelerator) from October, 1985, to May, 1991.Eleven patients were initially treated with x-ray at doses of16.2-50.4 (mean 42.5) Gy, followed by proton beam at doses of30.0-52.9 (mean 37.6) Gy. The other four patients were treatedwith proton beam alone at total doses of 75.0-88.5 (mean 81.4)Gy. The mean total dose for the 15 patients was 80.4 Gy. Asa result, the primary tumor lesions of all 15 patients disappearedand complete responses were obtained. Approximately four tofive months later, nine of the 15 patients developed esophagealulcer formations at the circumferences of their primary lesions.The ulcerations were healed, however, by conservative management.There was no evidence of local recurrence throughout the observationson six cases of superficial carcinoma. Among nine advanced carcinomapatients, three relapsed into esophageal carcinoma. Recurrenceswere observed eight, 16 and 44 months, respectively, after thetreatment. Ten of the 15 patients died, but eight died of otherdiseases. Three of four cases at autopsy did not show any cancercells in irradiated primary lesions. Four of the 15 patientslived for over five years. The results suggest that a high doseof irradiation delivered by a well-defined proton field couldresult in improved local control and long-term survival in esophagealcarcinoma without undue risk of injury to primary and adjacentorgans.     

Comparison of the prophylactic usefulness of epirubicin and doxorubicin in the treatment of superficial bladder cancer by intravesical instillation: a multicenter randomized trial

A multicentric randomized trial was conducted for the purpose of investigating the prophylactic efficacy of intravesical epirubicin instillation following transurethral resection of superficial bladder cancer in comparison with the efficacy of doxorubicin. The patients were centrally randomized into 2 groups and received 19 intravesical instillations of epirubicin or doxorubicin at 30 mg/30 ml physiological saline twice a week for 4 weeks and then once monthly for 11 months. A total of 150 patients with Ta and T1 superficial bladder cancer were entered in the trial, and 114 were evaluable. The nonrecurrence rates determined for each group at 1 and 2 years by the Kaplan-Meier method were 92.8% and 88.6%, respectively, for the epirubicin group and 86.4% and 81.7%, respectively, for the doxorbicin group. The differences between the two groups were not statistically significant. The main side effects encountered in this study were symptoms of bladder irritation such as micturitional pain, pollakisuria, and hematuria. The respective frequencies of those symptoms were 10%, 15.0%, and 5.0% in the epirubicin group and 14,8%, 14.8%, and O in the doxorubicin group. These results suggest that epirubicin is a useful drug, comparable with doxorubicin, for intravesical instillation chemotherapy in the prophylactic treatment of superficial bladder cancer.Paper presented at the 5th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 24–25 September 1993, Hakone, Japan     

Nutrient and shunt flow responses to vidian nerve stimulation in nasal and facial tissues of the dog

Summary The potency of parasympathetic vasomotor efferent nerves in controlling blood flow of the face and nose was indicated by the following features attributed to the maxillary artery and their vascular compartments in dogs. Electrical stimulation of the vidian nerve induced a frequency-dependent increase in maxillary flow, which was due to a significant decrease in resistance to flow in nutrient and shunt vessels. Pronounced increases in perfusion rates mainly occurred in evaporative tissues of the nose, in particular the naso-maxilloturbinates and alar fold during vidian nerve stimulation, while those, for example, of the skin remained unchanged. Adrenergic and subsequent cholinergic blockade left the response pattern of maxillary flow to vidian nerve stimulation basically unaffected. Both nutrient and shunt flows contributed to the parasympathetically induced increases in maxillary flow while responses were compartmentalized similar to that found in untreated animals. Apart from sympathetic vasoconstrictor inputs, these results show that cholinergic and non-cholinergic parasympathetic vasodilator inputs contribute to the adjustment of vasomotor tone in the maxillary vascular bed. Offprint requests to: K. Pleschka     

Prognostic variables in patients with upper urinary tract cancers

Background We conducted a retrospective analysis of patients with upper urinary tract cancers in order to examine the usefulness of some clinicopathological factors as prognostic predictors. Methods Between January 1985 and December 1994, 74 patients underwent surgical treatment for primary upper urinary tract cancers. Clinicopathological patient data were examined based on the criteria of The Japanese Urological Association. Results In this series, 40 tumors were located in the renal pelvis, 30 in the ureter, and 4 in both the renal pelvis and ureter. Associated bladder cancers were found in 27 patients. Histopathological examination revealed that the tumor grade was grade 1 or grade 2 in 45 patients and grade 3 in 29 patients; the pathological stage was Ta or T1 in 36 patients, and T2, T3 or T4 in 38 patients. Vascular invasion was found in 34 patients. The 5-year survival rates were 53% for all patients, 73% for patients with grade 1 and 2 tumors, and 28% for those with grade 3 tumors (P<0.0005) 70% for patients with stage Ta and T1 tumors, and 36% for those with stage T2, T3, and T4 tumors (P<0.005); 89% for patients without vascular invasion and 0% for those with vascular invasion (P<0.0001). Multivariate analysis revealed a strong independent correlation of vascular invasion with poor prognosis. Conclusions Tumor grade, pathological stage, and vascular invasion were significantly important prognostic parameters in patients with upper urinary tract cancers, and among them only vascular invasion was an independent predictor of poor prognosis.     

Tilting operating table with self-control foot switch: a new neurosurgical tool

BACKGROUND: Observation of the surgical field from all directions is essential in microneurosurgery. A tilting operating table operated by the surgeon can satisfy this need. METHODS: A tilting operating table operated by the surgeon using a foot switch was developed by modifying the Sugita table incorporating the X-Y shifter. RESULTS AND CONCLUSIONS: The modified operating table allows the surgeon to move the patient in the head up or down directions, as well as the left side down or right side down directions, so the surgical field can be inspected from all aspects without changing the vertical axis of the operating microscope.     

Snare technique of vascular transposition for microvascular decompression--technical note

Recurrence of trigeminal neuralgia (TN) or hemifacial spasm (HFS) after microvascular decompression (MVD) is not rare. The prosthesis material eventually adheres to the neurovascular structures and again transmits arterial pulsation to the nerve. A snare ligature technique using a Gore-Tex tape can be used for the transposition of the offending artery. No prosthesis is necessary once the transposition is complete. This technique requires introduction of either Gore-Tex tape or thread around the artery and suture over the petrous dura, so an adequate working space as if operating in a shallow basin is essential. Therefore, the osteoplastic craniotomy is a little larger than usual with the scalp flap entirely reflected using a semicircular skin incision. The Gore-Tex tape can be directly snared around the artery and sutured over the petrous dura. If this procedure is difficult, a thread can be attached to both ends of the Gore-Tex tape to pass the tape around the vessel. Seven patients with TN and 13 patients with HFS have undergone this surgery. Although the follow-up period is not yet long enough, there has been no case of recurrence. The present technique for MVD can provide complete and permanent transposition of the offending artery.