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.

Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function.

BACKGROUND: Recently, it has been reported that frequent premature ventricular contractions (PVCs) may be associated with causing heart failure in patients with left ventricular (LV) dysfunction. However, the prognostic significance of frequent PVCs in asymptomatic patients with a normal LV function is unclear. METHODS: Two hundred and thirty-nine consecutive patients presenting with frequent PVCs (>1000 beats/day) originating from the right or left ventricular outflow tract without any detectable heart disease were enrolled in the study. Structural heart disease was ruled out by echocardiography and cardiac magnetic resonance imaging, and Holter-ECG monitoring was repeated two or three times to evaluate the PVC prevalence at the initial evaluation. All patients were followed up for at least 4 years, and further observation was continued if possible. RESULTS: During an observation period of 5.6 (1.7) years, no patients exhibited any serious cardiac events. Although there was no significant change in the mean LV ejection fraction (LVEF) and mean LV diastolic dimension (LVDd), there was a significant negative correlation between the PVC prevalence and DeltaLVEF (p<0.001) and positive correlation between the PVC prevalence and DeltaLVDd (p<0.001). When the development of LV dysfunction was defined as DeltaLVEF>-6%, 13 patients exhibited LV dysfunction. For the prediction of the development of LV dysfunction, PVC prevalence and LVEF at the initial evaluation were independent predicting factors (p<0.01). CONCLUSION: Although the prognosis in patients with frequent PVCs was considered relatively benign, attention should be paid to the progression of the LV dysfunction during a long-term observation, especially in patients with a high PVC prevalence.

Antibody response of lions inoculated with inactivated calicivirus vaccine experimentally prepared.

The majority of lions and tigers in a Safari park in Japan were suffering from acute vesicular disease caused by a calicivirus infection. All of these animals were injected subcutaneously with an inactivated calicivirus vaccine experimentally prepared with one of the seed viruses originally isolated from sick lions. Seroneutralizing antibody of paired sera collected from ten female lions at two week intervals was measured. A significant elevation of specific antibody was detected in the serum samples and no local or systemic reactions associated with vaccination were observed.

A strain of calicivirus isolated from lions with vesicular lesions on tongue and snout.

In December 1992, 17 African lions and 7 Siberian tigers in a Safari park in Japan became sick with characteristic clinical symptoms of acute vesicular formations on tongue and snout. The disease was highly contagious since all of these animals showed similar symptoms within two days after the onset of the first case. Swabs were taken from affected animals in rubbing tongues, snouts and some from rectums. Cytopathic viruses were isolated on CRFK cell culture by virological tests. The physicochemical property of a representative virus strain, named Arthur/L, isolated from a male lion was identified as a member of Caliciviridae. However, seroneutralization test indicated that this virus strain was antigenically distinct from Japanese isolates of feline caliciviruses used for comparison. Viral capsid proteins of the present isolate, Arthur/L, and of a feline calicivirus, strain FC7, were compared in an electrophoresis in SDS-PAGE gel. The major viral capsid polypeptide of them were proved to be significantly different in molecular weight. The polypeptide of FC7 was estimated to be ca. 63 KDa whereas that of Arthur/L consisted of 2 components of ca. 65 and 62 KDa. The viral proteins of these two strains were also proved to be distinct by an immunoblotting test.

Granulomatous lesions caused by Pseudomonas aeruginosa in the ostrich (Struthio camelus).

Granulomatous lesions were observed in imported ostriches aged 3 months. Clinically, the birds showed lassitude, incoordination, and inappetence. At necropsy, yellowish white nodules often accompanied by a pseudodiphtheritic membrane were found in the oral, pharyngeal, tracheal and air sac mucosae, the lungs, oesophageal serosa, and abdominal peritoneum. Histopathological examination revealed purulent granulomatous lesions containing central bacterial colonies with an outer shell and club formation. The bacteria were small Gram-negative bacilli, which showed positive immunohistochemical staining for Pseudomonas aeruginosa. The bacterial colonies were positive for chicken IgM. Clubs around the colonies were negative for P. aeruginosa and chicken IgM. Such findings have not previously been reported in the ostrich.