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An incremental positivity of telomerase was observed during hepatocarcinogenesis. The use of this assay in 21-G-needle biopsy specimens may be useful in clinical examination.

SUMMARY1. The effect of acetylcholine (ACh) on the membrane current components in guinea-pig papillary muscle was studied by the single sucrose gap voltage clamp method.2. The slow inward current (i.) elicited by various depolarizations from the holding potential of -40 mV was evidently diminished by ACh greater than 5 x 10-7 M. The amplitude of i5, estimated as the difference between the peak of i.and the current at 150 msec, was reduced to 56-8 + 12-9 % (mean + S.D., n = 34) by 2 x 10-6 M-ACh when estimated at the membrane potential where the amplitude was maximal.3. is was suppressed almost completely by 2 mM-Co2+. i8 obtained by subtracting the current remaining in 2 mMCo2+ was also diminished to the same extent by 2 x 10-6 M-ACh with little change in its time course; the degree of decrease was not dependent on the membrane potential.4. The time-dependent outward current during the depolarizing pulse was also diminished by 2 x 10-6 M-ACh. Correspondingly, the positive tail current obtained when the membrane was repolarized to the holding potential of -40 mV after various 1 see depolarizations was reduced in a proportionate manner to 68-6 + 7-3 %

HARUSHIGE NAKATSUKASA, KOUZOU ASHIDA, TOSHIHIRO HIGASHI, SOUHEI OHGUCHI, SO TSUBOI, NAOKI HINO, KAZUHIRO NOUSO, YOSHIAKI URABE, NOBUYUKI KINUGASA, KEIGO YOSHIDA, SHUJI UEMATSU, MASAHIKO ISHIZAKI, YOSHIYUKI KOBAYASHI, AND TAKAO TSUJI Hepatocellular carcinoma (HCC) is one of the most prevaThe cellular distribution of tissue inhibitor of melent malignancies in Japan and China, and frequently occurs talloproteinases (TIMP)-1, and TIMP-2 was studied by in hepatitis B or C virus-related chronic hepatitis or cirrhousing in situ hybridization in surgically removed husis. In particular, cirrhosis has been regarded as a high-risk man hepatocellular carcinomas (HCCs) and cholandisease state for developing HCCs. A unique feature of HCC giocellular carcinomas (CCCs). The purpose of this development is the occurrence of the tumor in fibrotic or cirstudy was to characterize the potential involvement rhotic liver that contains abundant extracellular matrices of TIMPs in the development of HCCs and CCCs. All (ECMs). Therefore, the capacity of HCC to degrade the surHCCs and CCCs expressed TIMPs. The distribution rounding ECMs may be an important trait for growth, invaof transcripts for TIMPs in the tumors was mostly sion, and metastasis. homogeneous. Expression of TIMPs in cancer cellsThe characteristic features of malignant tumors are the was more intense than that in the surrounding noninvasion to cross tissue boundaries and the metastasis to cancerous liver (either, cirrhosis, chronic hepatitis, distant organs. Many steps that occur during cancer invasion or normal), and expression of TIMP-1 was stronger and metastasis require specific interactions between maligthan that of TIMP-2. Expression of TIMPs varied nant cells and the ECMs, 1 particularly in regard to HCC and among HCC nodules, but there was no obvious associcirrhotic liver. Multiple humoral factors are involved in this ation between the expression level of TIMPs and difprocess: matrix metalloproteinases (MMPs), tissue inhibitor ferentiation stages or invasiveness of the HCCs. Tranof metalloproteinases (TIMPs), and various cytokines. An imscripts for TIMPs were clearly demonstrated in the balance between TIMPs and MMPs may be an important metastatic HCC nodules in the lung. Expression of factor in tumor invasion and metastasis. TIMP-1 in CCC was strong, and small nodules of CCC Three members of the TIMP family have been described. 2 were recognized in the liver. ImmunohistochemicalEach TIMP is the product of a separate gene. TIMP-1 is a 28-study for TIMP-1 revealed a consistent staining of the kd glycoprotein, whereas TIMP-2 is a 21-kd nonglycosylated TIMP-1 protein with the transcripts. In the perituprotein. Between TIMP-1 and TIMP-2, there is 37% amino moral histologically normal liver, which was not inacid identity and 65.6% overall homology. 3 TIMP-3 has been fected with either hepatitis B or C virus, expression identified as a 21-kd protein and shares an amino acid seof TIMP-1 was found in various cell types, but that of quence homology of 40% with TIMP-1 and 45%...

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