Masaru Baba

Inactivation of SSI-1, a JAK/STAT inhibitor, in human hepatocellular carcinomas, as revealed by two-dimensional electrophoresis

BACKGROUND/AIMS Hepatocellular carcinoma (HCC) is one of the most common human cancers, and many efforts have been paid to discover aberrant expression control in HCC, however the specific molecular mechanisms involved in hepatocarcinogenesis remain to be determined. METHODS To investigate genomic changes that occur in human primary hepatocellular carcinomas (HCC), we carried out restriction landmark genomic scanning. This two-dimensional electrophoretic system displays 2000-3000 NotI-landmark sites in a single gel. RESULTS We detected one landmark spot that showed diminished signal intensities in a majority of the HCCs we examined. Cloning revealed that this spot represented a NotI-cluster sequence that was enriched with CpG dinucleotides in the promoter region of a gene encoding Janus kinase (JAK)-binding protein, SSI-1 (also known as JAB1 or SOCS-1). Expression of the SSI-1 gene was markedly reduced in half of eight HCCs analyzed. CONCLUSIONS This protein regulates the Janus kinase signal transducers and activators of transcription signal transduction pathway, which transmits signals from cytokines to the intracellular apparatus. These data suggest that dysregulation of the pathway relate with progression of HCC.

Chronic hepatitis C associated with monoclonal gammopathy of undetermined significance

Background: Two patients were admitted to Mie Prefectural General Medical Center and diagnosed as chronic hepatitis C complicated with monoclonal gammopathy of undetermined significance (MGUS).

A case of allergic liver injury induced by tegafur.

A 51-year-old woman constitutionally susceptible to allergy presented with acute allergic liver injury. She was taking tegafur for treatment of carcinoma of the uterus. The acute liver injury appeared 3 weeks after the first drug administration. She had marked elevation of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT), moderate jaundice, and eosinophilia. The virus markers revealed hepatitis B surface antigen (HBsAg) (-) antibody to hepatitis B surface antigen (HBsAb) (+), and immunoglobulin M HA antibody (IgM HA Ab) (-). The laparoscopic and histologic findings were compatible with drug-induced liver injury. Further, the results of the lymphocyte stimulation test (LST) and challenge test by tegafur were positive. From the above findings, the liver injury was diagnosed to be an allergic reaction induced by tegafur. The hepatic function returned to normal about 20 days after tegafur administration was suspended. Allergic liver injury induced by tegafur is very rare. We report the case with a short review of the literature.

DNA alterations during multi-step development of human hepatocellular carcinomas revealed by laser capture microdissection

In order to clarify early molecular events involved in liver carcinogenesis, we analyzed 53 liver-cirrhosis nodules (LCNs) from five patients and 13 micro-hepatocellular carcinoma (HCC) nodules from one patient and looked for alterations of microsatellites in genomic DNA after carefully preparing the tissue samples by laser-capture microdissection (LCM). Allelotyping was done with 20 markers corresponding to anonymous microsatellites and 13 corresponding to tumor suppressor genes (TSGs) that had shown significant alterations in HCCs. We detected both loss of heterozygosity (LOH) and microsatellite shifts (MS). Overall, 24 of 53 (47%) of LCNs showed LOH with any of the informative markers used in the study, reflecting that proportion of LCNs with clonal growth. The fractional allelic loss (FAL) index, an indication of total genomic complexity, was not significantly different between LCN and micro-HCC nodules, but their profiles of alteration were different. These profiles were classified into three groups: (1) LCN profile-allelic loss at chromosomal arms 1q and 14q, TBP and BRCA1; (2) HCC profile-LOH at 4q, 6q, 7q, 17p, NF1, IGFIIr and p53 in micro-HCC nodules; these changes in early lesions were identical to those seen in mature HCCs; (3) Common profile-LOH at NF1 and 6q, including IGFIIr, common to both LCN and HCC. No LCN showed LOH at p53 and Rb, loci that are generally altered in HCCs. However, 12 intra-tumoral nodules examined had lost p53 in all informative cases, although the loss of Rb was a late event. These results suggest that early genomic profiles confined to LCNs, and additional profiles that can be observed when liver tissue undergoes malignant transformation, support a model of multi-step development of HCC.

A Reevaluation of the Glucagon Provocative Test for Pheochromocytoma

The effects of glucagon on the adrenergic system have been studied in experimental and clinical conditions. 1. in vitro studies: In the first experiment a continuous flow incubation system was developed in which the secretory response to these drugs was characterized by a serial fluorimetric assay of catecholamines in the effluent medium. Pig adrenal medulla or human pheochromocytoma were studied. There was an initial massive release of catecholamines which declined to basal levels (0.02 micrograms/mg) after 1.5 hours. When 10(-4) glucagon was infused for 10 minutes following 2 hours of preincubation, both adrenaline and nonadrenaline outputs rose abruptly to concentrations of 0.08 micrograms/mg and 0.07 micrograms/mg respectively. In the second experiment the effect of these drugs on the in vitro release of catecholamines from the isolated in vitro chromaffin granules of the pig adrenal medulla were studied. The results were the same as in the previous experiment. 2. clinical studies: The effects of glucagon were studied on the blood pressure and urinary catecholamine levels of healthy control subjects, of patients suffering from essential hypertension, thyroid disease, diabetes mellitus and acromegaly. Glucagon induced a slight but constant increase in blood pressure. By contrast no significant urinary catecholaline elevation was evoked. There was no difference in the effect of intravenous glucagon between normal subjects and patients suffering from the above-mentioned disorders.

The Diagnosis of Legionella pneumophila Serogroup 5 Bacteremic Pneumonia during Severe Neutropenia Using Loop-mediated Isothermal Amplification

A 60-year-old man developed pneumonia after undergoing autologous peripheral blood stem cell transplantation for diffuse large-B cell lymphoma. A urinary antigen test and sputum culture were both negative for Legionella pneumophila; however, a sputum sample that was examined by loop-mediated isothermal amplification (LAMP) was positive for Legionella spp. On admission, the results of blood culturing using a BACTEC system were negative for 7 days. However, L. pneumophila serogroup 5 was detected in a blood subculture using WYOα medium. The patient was successfully treated with a fluoroquinolone-based regimen. LAMP is useful for the diagnosis of Legionella spp.