Blockade of Rho/Rho-associated coiled coil-forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase-dependent manner

Aim:  There is growing evidence that the Rho/Rho-associated coiled coil-forming kinase (ROCK) signaling pathway is upregulated in tumors and plays a key role in cancer invasion and metastasis. Our aim was to test the anticancer effects of Rho/ROCK inhibitor, Y-27632, including possible mechanisms in a highly-metastasizing hepatocellular carcinoma (HCC) mouse model on its secretion of matrix metalloproteinase (MMP) and tumor progression.
Methods:  Following orthotopic implantation of CBO140C12 HCC tumor fragments into the liver of mice, the mice were randomly assigned to a Y-27632-treated group or control group. After treatment for 4 weeks, specimens were obtained to evaluate tumor size, metastases, and immunohistochemical findings. In vitro , we examined the effects of Y-27632 and RhoC siRNA on MMP-2 and -9 expressions, invasiveness, and apoptosis in cultured tumor cells.
Results:  Both RhoA and RhoC were upregulated in HCC-bearing livers, and Y-27632 significantly inhibited not only tumor growth and intrahepatic metastasis ( P  < 0.05), but also tumoral MMP-9 expression. Moreover, Y-27632 treatment resulted in large necrotic areas in tumors. In vitro , Y-27632 and RhoC siRNA reduced MMP-2 and -9 expressions, as well as the chemotactic migration of tumor cells dose-dependently, and increased apoptosis eight times.
Conclusion:  Y-27632 suppresses progression and limits the intrahepatic metastasis of established HCC. This could be linked to the decreased MMP expression and induction of apoptosis in tumor cells. Rho signaling may prove to be a productive target in anticancer therapy.     

Anatomical basis of hepatic venographic alterations in idiopathic portal hypertension

ABSTRACT— Hepatic venograms made in 40 authentic cases of idiopathic portal hypertension (Banti's syndrome) were compared with 13 normal venograms and venograms obtained in 88 cases of cirrhosis, and analyzed in the light of the pathological changes seen in 16 postmortem liver specimens. There were frequent anastomoses between hepatic vein radicles, approximation of middle-size branches to the liver surface, reduction in the angles between the main hepatic vein and its tributaries, and difficulty in opacifying portal vein branches in wedged retrograde portography. These angiographic alterations were corroborated by gross pathological findings which comprised displacement of middle-size hepatic vein branches closer to the liver surface and their approximation among themselves, and seem to be accounted for by the disappearance of liver parenchyma secondary to the peripheral portal circulatory failure.     

Angiographically documented coronary vasospasm as a cause of myocardial infarction during the acute phase of aortic dissection

Summary We angiographically documented coronary vasospasm which resulted in myocardial infarction during the acute phase of aortic dissection (Stanford A). Coronary and aortic angiography performed at admission of the patient revealed complete occlusion of the right coronary artery and dissection of the aorta. Intracoronary injection of isosorbide dinitrate and intravenous administration of verapamil opened the occluded right coronary artery and blood flow was fully restored. We conclude that, in this case of aortic dissection, the severe stimulation by the aortic dissection brought about vasospasm of the right coronary artery which was the major cause of myocardial infarction. This is the first case report showing clear evidence that myocardial infarction is brought about by vasospasm associated with aortic dissection.     

Complementarity determining region-III is a useful molecular marker for the evaluation of minimal residual disease in mantle cell lymphoma

Bone marrow (BM) and peripheral blood (PB) involvement in 10 patients with mantle cell lymphoma (MCL) was analysed by a polymerase chain reaction (PCR)-mediated RNase protection assay. The complementarity determining regions (CDR)-III of all 10 MCLs examined was amplified efficiently with consensus V_H and J_H primers by PCR, and BM and/or PB involvement was evaluated by RNase protection assay in all 10 patients examined. Our assay showed BM and/or PB of the entire group to have neoplastic cells at presentation, despite the fact that eight patients were found to have BM and/or PB involvement on the basis of morphological examination and/or surface marker analysis. We also examined minimal residual disease (MRD) after conventional chemotherapy, and detected MRD in a patient in complete remission (CR). Although previous studies have shown that t(11;14) breakpoint amplification by PCR was only applicable to about 30–40% of cases, the present study indicates that CDR-III is a useful molecular marker and the PCR-mediated RNase protection assay is a good tool for the evaluation of MRD in MCL. It is suggested that BM and PB of MCL patients are quite frequently involved at presentation and even after conventional chemotherapy at the molecular level.     

Enzyme histochemistry is useful to assess viability of tumor tissue after microwave coagulation therapy (MCT): metastatic adenocarcinoma treated by lateral segmentectomy after MCT

We report on a case of metastatic adenocarcinoma of liver that was removed and examined histochemically after microwave coagulation therapy (MCT). The patient was a 65-year-old woman who had a metastatic tumor in the liver (S3) after high anterior resection due to a rectal adenocarcinoma and received MCT against the tumor. One month after MCT, multiple metastatic tumors were detected by abdominal computed tomography (CT) scan. As it was difficult to control them by MCT alone, we performed lateral segmentectomy. To assess the effects of microwave ablation on cellular viability of metastatic tumor, we used enzyme histochemistry for acid phosphatase (AcP), which is positive in macrophages infiltrating in the tumor. In a part of the ablated area of resected liver, there was remaining neoplastic tissue of which the morphology was maintained in H&E staining. This was found to be microwave-fixed non-viable tissue because no enzyme activity of AcP was detected in the infiltrating macrophages. This case report suggests that enzyme histochemistry was useful to assess the effect of MCT, enabling us to distinguish fixed cells from viable cells.     

Early events in duck hepatitis B virus infection. Sequential appearance of viral deoxyribonucleic acid in the liver, pancreas, kidney, and spleen

Early events in duck hepatitis B virus infection were studied in 1-day-old ducklings following inoculation. Group A ducklings (n = 26) were inoculated intraperitoneally with 10 microliter of infective serum, and group B ducklings (n = 29) were inoculated with 50 microliter. Samples of the serum, liver, pancreas, kidney, and spleen were taken, starting 3 h after inoculation and continuing through the 14th day. In group A, relaxed circular double-stranded deoxyribonucleic acid (DNA) did not appear in serum until day 10, whereas single-stranded DNA, indicative of active replication of the virus, was already demonstrable in the liver on day 6. In group B, single-stranded DNA was first detected in the liver on day 3, and relaxed circular double-stranded DNA became detectable in the liver and serum on day 6. The pancreas started to have single-stranded DNA on day 10 in group A and on day 6 in group B, suggesting active viral replication in this organ soon after it occurred in the liver. In the spleen, relaxed circular double-stranded DNA was detectable when serum became positive for viral DNA, probably due to contamination by serum DNA. However, single-stranded DNA became detectable on day 14 in group A and on day 6 in group B, suggesting a delayed but active viral replication in the constituent tissues of the spleen. These results have demonstrated that active replication of duck hepatitis B virus starts in the liver after infection, and is followed by the pancreas, the kidney, and the spleen. The incubation period is shortened when larger amounts of virus are inoculated, but the sequential occurrence of viral replication in these organs remains the same.