Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma.

Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.

Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis.

Many transcription factors, particularly those involved in the control of cell growth, are unstable proteins destroyed by ubiquitin-mediated proteolysis. In a previous study of sequences targeting the transcription factor Myc for destruction, we observed that the region in Myc signaling ubiquitin-mediated proteolysis overlaps closely with the region in Myc that activates transcription. Here, we present evidence that the overlap of these two activities is not unique to Myc, but reflects a more general phenomenon. We show that a similar overlap of activation domains and destruction elements occurs in other unstable transcription factors and report a close correlation between the ability of an acidic activation domain to activate transcription and to signal proteolysis. We also show that destruction elements from yeast cyclins, when tethered to a DNA-binding domain, activate transcription. The intimate overlap of activation domains and destruction elements reveals an unexpected convergence of two very different processes and suggests that transcription factors may be destroyed because of their ability to activate transcription.

Evaluation of a new test for colorectal neoplasms: a prospective study of asymptomatic population.

In a recent pilot study, we have suggested of potential usefulness of a new test (Shams' test) for screening colorectal (CR) cancer in Japan. Although the sensitivity of this test was remarkably high, its accurate specificity was unclear. The purpose of our present study is to evaluate the incidence of non-specific reaction of Shams' test in the normal Japanese populations. We analyzed 330 asymptomatic individuals, who were seen for annual health checkup, for the presence of the tumor marker D-Gal-B (1- > 3)-D-GalNAc in their rectal mucin. The rectal mucin was smeared on nitrocellulose membrane filter and developed by a sequential reaction of B-D-galactose oxidase and Schiff's reagent. Immunological fecal occult blood test (FOBT) was done in parallel. Extensive study by barium enema/total colonoscopy was indicated only for those who showed positive results with Shams' test or FOBT. A total of 271 individuals were negative, while 50 and 9 had positive and equivocal (+/-) results, respectively. Subsequent barium enema and fiberoptic proctocolonoscopic examinations, which were available on 32 of 59 cases, revealed 6 adenomatous polyps, one villous adenoma with focal severe atypia, and 4 cases of diverticular disease. Except for one patient with polyp, 6 other patients harboring polyps were negative with immunological FOBT. The overall specificity of Shams' test was 92.2% (271/294). Based on these results and preceding reports, we concluded that Shams' test could be a useful tool in our strategy for early detection of CR neoplasms and precancerous lesions.

[Changes in the blood cell counts with aging].

We analyzed the blood cell counts and serum levels of total protein (TP), total cholesterol (TC) and triglyceride (TG) of 2,231 healthy subjects (1,295 men and 936 women) between age 20 and 99 years in order to clarify the following two subjects. (1) In the approximately 10 years since the report of Shirakura et al in 1978, eating habits have improved and the average life expectancy has extended in Japan. Is there any effect of such betterment on blood cell counts of the aged? (2) It has been pointed out that quality of everyday life, such as staying at home but not in an old-age home, working, traveling, and so forth, had an influence on the blood cell counts of aged. Is there any difference between the blood cell counts of people under 60 years and those of people older than 60 years who have a good quality of life as mentioned above? The hemoglobin concentration, red blood cell count, and hematocrit value began to decrease in men in their sixth decade and in women in their seventh decade and the change was more prominent with advancing age, especially in men. The white blood cell count and platelet count tended to decrease with advancing age. The serum levels of TP, TC, and TG also declined with age in those over 60 years of age. These results confirmed that the hemoglobin concentration, red blood cell count, and hematocrit value decrease in the elderly subjects as they grow older and it may be considered that reduced ingestion of protein is one of the causes of the phenomenon.

Ultrastructural study of two subtypes of gastric adenoma.

An ultrastructural study was performed to identify any differences in fine detail between type III and IV gastric polyps, which seem to differ from each other because they have different histological features and malignant potential. Clear ultrastructural differences were found, implicating microvilli, mucous granules, interdigitations, ribosomes, mitochondria and nuclei. Although these two subtypes have often been grouped together as borderline lesions or adenomas, the findings imply that they should be treated as essentially different.

Liposarcoma of the breast, review of the literature and a report of a case.

A case of gigantic liposarcoma of the breast in a 52-year-old woman was reported. She had a small indolent mass in the left breast for twenty years. The mass grew rapidly from the summer of 1979 and became gigantic and penetrated the skin over the mass. Her general condition on admission was poor but resection of the tumor was carried out. She suddenly died of cardiac failure with electrolytes imbalance 13 days after the operation. The diagnoses of liposarcoma, predominantly myxoid, was made on the basis of light and electron microscopic findings. Forty cases of liposarcoma of the breast were collected from the literature. The possibility of malignant transformation of a benign tumor was suggested.