Aberrant activation of the mTOR pathway and anti-tumour effect of everolimus on oesophageal squamous cell carcinoma

Background:

The mammalian target of rapamycin (mTOR) protein is important for cellular growth and homeostasis. The presence and prognostic significance of inappropriate mTOR activation have been reported for several cancers. Mammalian target of rapamycin inhibitors, such as everolimus (RAD001), are in development and show promise as anti-cancer drugs; however, the therapeutic effect of everolimus on oesophageal squamous cell carcinoma (OSCC) remains unknown.

Methods:

Phosphorylation of mTOR (p-mTOR) was evaluated in 167 resected OSCC tumours and 5 OSCC cell lines. The effects of everolimus on the OSCC cell lines TE4 and TE11 in vitro and alone or in combination with cisplatin on tumour growth in vivo were evaluated.

Results:

Mammalian target of rapamycin phosphorylation was detected in 116 tumours (69.5%) and all the 5 OSCC cell lines. Everolimus suppressed p-mTOR downstream pathways, inhibited proliferation and invasion, and induced apoptosis in both TE4 and TE11 cells. In a mouse xenograft model established with TE4 and TE11 cells, everolimus alone or in combination with cisplatin inhibited tumour growth.

Conclusion:

The mTOR pathway was aberrantly activated in most OSCC tumours. Everolimus had a therapeutic effect both as a single agent and in combination with cisplatin. Everolimus could be a useful anti-cancer drug for patients with OSCC.     

Über die Lokalisationsbestimmung bei chirurgischen Erkrankungen des Centralnervensystems mittels der Chronaxie

Zusammenfassung An der Hand von 50 klinischen Untersuchungsergebnissen wird gezeigt, da? die Chronaxiebestimmung als diagnostisches Hilfsmittel bei chirurgischen Krankheiten des Centralnervensystems den bisher gebr?uchlichen physikalischen Verfahren an Exaktheit überlegen ist. Mit 2 Textabbildungen.     

Effect of pyridoxine-deficiency on degradation of cytosolic aspartate aminotransferase in rat liver lysosomes.

Highly purified lysosomes were isolated from the livers of control and pyridoxine-deficient rats. The calculation of the lysosomal protein contents indicated that the livers of both groups of rats contain virtually the same amounts of the lysosomal proteins (12.0 and 13.0 mg lysosomal proteins/g liver proteins for the control and pyridoxine-deficient rats, respectively). The immunoblotting of the lysosomal proteins with anti-cytosolic aspartate aminotransferase (cAspAT) showed 46 kDa band, corresponding to the subunit molecular weight of cAspAT, as well as the bands representing degradative intermediates of cAspAT. The relative amounts of the immuno-reactive substances were estimated by scanning the immuno-stained bands and measuring the densitometric tracings. It was found that the lysosomes in the pyridoxine-deficient rat liver contain almost twice as much cAspAT and its degradative intermediates as those in the control rat liver. On the basis of these observations, it was concluded that the increased rate of degradation of cAspAT in the liver of the pyridoxine-deficient rats is brought about by the increased rate of sequestration of cAspAT into lysosomes.     

A method of interval estimation for number of patients in the nationwide epidemiological survey on intractable diseases]

A method for estimating the intervals for the number of patients with intractable diseases from nationwide epidemiological surveys was developed under the assumption that response is independent of frequency of patients. This method is based on data utilizing the number of response hospitals classified by their reported number of patients. The approximate 95% confidence intervals of numbers of several intractable diseases patients were estimated using this method.     

Activation of natural cytotoxic activity and concomitant reduction of triglyceride content of murine spleen, treated with an antitumor antibiotic, ascofuranone

Ascofuranone (AF) elevated natural cytotoxic activity of spleen when it was administered intraperitoneally to male mice. The elevation was observed both in low and high responder mice. AF-activated splenocytes lysed NK-resistant tumor cells, FM3A, P388 and sarcoma 180 cells as well as NK-sensitive YAC-1 cells. However, AF suppressed other lymphatic functions such as mitogenic responses and interleukin 2 production. Because AF did not activate splenic NK activity in vitro, the activation is assumed to be caused by a host-mediated process. One of the possibilities is modulation of the lipid metabolism of splenocytes. Thus, we examined splenic lipid contents and revealed that AF decreased splenic triglycerides without affecting other lipids. In contrast, the antibiotic significantly increased triglyceride in muscle.     

Endoscopic microwave coagulation therapy for villous adenoma of the duodenum--a case report.

The effects of endoscopic microwave coagulation therapy on duodenal adenoma in a 58-year-old man are reported. The patient had a 35-mm sessile tubulo-villous adenoma in the duodenal bulb. Endoscopic polypectomy followed by microwave coagulation therapy for duodenal adenoma was performed to avoid a major surgical procedure which would disturb the physiological functions of the gastrointestinal tract. After partial polypectomy which included the core of the adenoma, the entire remaining adenoma was destroyed after three microwave therapy sessions. During a follow-up period of 14 months, neither endoscopic nor histologic evidence of recurrence has been noted. Endoscopic microwave coagulation therapy is considered to be useful in the treatment of large sessile duodenal villous adenoma, provided that repeated endoscopic follow-up surveillance is also performed.     

Poststatin, a new inhibitor of prolyl endopeptidase, produced by Streptomyces viridochromogenes MH534-30F3. I. Taxonomy, production, isolation, physico-chemical properties and biological activities

Poststatin, a new inhibitor of prolyl endopeptidase (PEP) was discovered in the fermentation broth of Streptomyces viridochromogenes MH534-30F3. It was purified by Diaion HP-20, Sephadex LH-20 and YMC-gel (ODS-A) column chromatography and then isolated as a colorless powder. Poststatin has the molecular formula C26H47N5O7. The IC50 value of poststatin against the PEP of partially purified porcine kidney was 0.03 microgram/ml. It has low acute toxicity. No deaths occured after iv injection of 250 mg/kg of this agent to mice.     

A case report of ovarian squamous cell carcinoma developing into a dermoid cyst with malignant transformation--immunohistochemical study

A histopathological and immunohistochemical study has been made on a case of an ovarian cancer that developed into a dermoid cyst with a malignant transformation. The case involved a 64-year-old married woman and her clinical grading was determined as being in Stage Ia (i). The ovarian tumor, weighing 1550 g, consisted of large cystic and small solid parts, and a well-differentiated squamous cell carcinoma (large cell, keratinized type) was observed in the solid part. By using an immunoperoxidase technique (the ABC method), the SCC was found to be positive in many cancer cells and the TPA also was positive in some cancer cells, though both the CEA and AFP were found to be negative.     

Effects of the new antiallergic drug 11-oxo-11H-pyrido[2,1-b] quinazoline-2-carboxylic acid on immediate allergic reactions

The effects of 11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid (Sm 857) on immediate type, particularly type I allergic reactions were investigated and the following results were obtained. 48-h homologous passive cutaneous anaphylaxis (PCA) in rats was inhibited by oral administration of Sm 857 from the 4th h to the 30th min before antigen challenge and by intravenous administration from the 2nd h to just before antigen challenge. 48-h homologous PCA in rats was inhibited dose-dependently by oral administration of Sm 857 at 1-50 mg/kg 30 min before antigen challenge. On the other hand, the intravenous administration 10 min before antigen challenge showed similar dose-dependent effects on PCA and the effects were significant at doses of 0.5-2 mg/kg. The oral administration of Sm 857 for 1-4 weeks reduced the PCA inhibitory effect in comparison with single administration. Sm 857 injected intravenously twice at intervals of 15-120 min showed no change in inhibitory effect. The PCA inhibitory effect of Sm 857 in adrenalectomized rats was reduced markedly when compared with that in sham-operated rats. On the other hand, adrenalectomy had no influence on the inhibitory effect of tranilast. Sm 857, tranilast and ketotifen inhibited histamin-induced capillary permeability in rats and, in particular, the effect of ketotifen was conspicuous. Sm 857, tranilast and ketotifen significantly inhibited antigen-induced histamine release from the peritoneal cavity of passively sensitized rats. Release of slow reacting substance of anaphylaxis (SRS-A), on the other hand, was inhibited significantly by Sm 857 and ketotifen. Sm 857 showed a tendency to inhibit antigen-induced histamine release from the lung tissue of passively sensitized guinea pigs and significantly inhibited SRS-A release. Sm 857 inhibited histamine- and leukotriene D4 (LTD4)-induced contraction in the lung parenchyma and the tracheal muscle. However, the drug had no effect on contraction of the ileum. Sm 857 showed a tendency to inhibit the Schultz-Dale reaction in the lung parenchyma ana the ileum. Both oral and intravenous administration of Sm 857 showed an inhibitory effect on experimental asthma in guinea pigs, which was similar to that of tranilast.