Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier.

BACKGROUND: In surface antigen of hepatitis B virus (HBsAg)-positive carrier for anticancer treatment of malignant lymphoma, it is well recognized that reactivation of hepatitis B virus (HBV) occasionally occurs. However, there have been only a few studies of HBV reactivation in serum HBsAg-negative and hepatitis B core antigen (HBcAb)-positive occult HBV carriers. We looked at both retrospective and prospective studies to determine the prevalence, clinical course and risk factor of HBV reactivation during chemotherapy in lymphoma patients. PATIENTS AND METHODS: Forty-eight of 127 (37.8%) lymphoma patients were HBsAg negative and HBcAb positive, and 24 of these patients were then given liver function tests and HBsAg tests monthly and serum HBV DNA every 3 months. RESULTS: HBV reactivation was observed in two patients (4.1%) who had received intensive chemotherapy including steroid and rituximab. Immediate administration of entecavir therapy after elevation of HBV DNA level was conducted, and this resulted in reduction of it and improvement of liver function test. CONCLUSIONS: Rituximab plus steroid-containing regimens may increase the risk of HBV reactivation in HBsAg-negative and HBcAb-positive lymphoma patients. More ambitious prospective studies are required to establish clinically useful or cost-effective follow-up methods for control of HBV reactivation in lymphoma patients with occult HBV infection.

Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc.

Embryonic stem (ES) cells are self-renewing, pluripotent cell lines, characterized by their potential to differentiate into all cell types. The proto-oncogene product c-Myc has a crucial role in the self-renewal of mouse ES (mES) cells, but its role in human ES (hES) cells is unknown. To investigate c-Myc functions in hES cells, we expressed an inducible c-Myc fused to the hormone-binding domain of the estrogen receptor (c-MycER) protein that is activated by 4-hydroxy-tamoxifen. In contrast to its role in mES cells, activation of c-MycER in hES cells induced apoptosis and differentiation into extraembryonic endoderm and trophectoderm lineages concomitant with reduced expression of the pluripotent markers Oct4 and Nanog. Neither inhibition of caspase activity nor knockdown of p53 by RNA interference impaired the induction of differentiation markers induced by c-Myc activation. In addition, differentiation induced by c-Myc activation was associated with downregulation of alpha6 integrin expression, suggesting an important role for the integrin/extracellular matrix interaction in the regulation of ES cell behavior. None of these effects occurred with deletion of the c-Myc transactivation domain, indicating that c-Myc promotes both apoptosis and differentiation in a transcriptional activity-dependent manner. Together, our results provide new insights into the c-Myc functions regulating hES cell fate.

[Effect of sumatriptan on cerebral blood flow during migraine headache: measurement by sequential SPECT used 99mTc-ECD background subtraction method].

The present study was designed to examine the effect of sumatriptan on regional cerebral blood flow (CBF) during migraine headache. Nine cases were examined by 99mTc-ECD background subtraction method for the absolute value measurement of regional CBF before and after sumatriptan injection. rCBF except for occipital and perioccipital lobes, were increased 10-20% during migraine headache and significant decreases were observed by sumatriptan injection. Two cases of nine had transiently increased systemic blood pressure and cardiac pulse rate, however, all cases improved migraine headache after injection of sumatriptan.

Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines.

Induction of procoagulant factors in malignant cells is considered to be the major cause of coagulation disorders in cancer. Thrombomodulin (TM), a negative regulator of coagulation was also found to be expressed in cancer cells. We report here evidence for another anticoagulant, the endothelial cell protein C receptor (EPCR), in cancer cells. EPCR was detected in several cell lines derived from various types of cancer. Significant levels of protein C (PC) activation were detected only with cell lines expressed both EPCR and TM. Anti-EPCR monoclonal antibodies (mAbs) specifically inhibited the activation. Thus, EPCR function appears to be important for PC activation by cancer cells. In addition, we detected EPCR expression in tumor cells from breast cancer patients, with an extremely high frequency. EPCR function may contribute to progression or pathogenesis of some types of cancer, and may explain the complexity of coagulopathy in cancer patients.

The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries.

Plasma protein C functions as an anticoagulant when it is converted to the active form of serine protease. Protein C activation has been found to be mediated by the endothelial cell surface thrombin/thrombomodulin (TM) complex. In addition, we recently identified the endothelial cell protein C/activated protein C receptor (EPCR) which is capable of high-affinity binding for protein C. In this study, we established monoclonal antibodies (mAbs) against EPCR including several function blocking antibodies. Immunohistochemical analysis using these mAbs demonstrated that EPCR is widely expressed in the endothelial cells of arteries, veins, and capillaries in the lung, heart, and skin. Function blocking anti-EPCR mAbs strongly inhibited protein C activation mediated by primary cultured arterial endothelial cells which express abundant EPCR. Anti-EPCR mAbs also prevent protein C activation mediated by microvascular endothelial cells. These results indicate that EPCR functions as an important regulator for the protein C pathway in various types of vessels.

Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor.

Protein C is an important regulatory mechanism of blood coagulation. Protein C functions as an anticoagulant when converted to the active serine protease form on the endothelial cell surface. Thrombomodulin (TM), an endothelial cell surface receptor specific for thrombin, has been identified as an essential component for protein C activation. Although protein C can be activated directly by the thrombin-TM complex, the conversion is known as a relatively low-affinity reaction. Therefore, protein C activation has been believed to occur only in microcirculation. On the other hand, we have identified and cloned a novel endothelial cell surface receptor (EPCR) that is capable of high-affinity binding of protein C and activated protein C. In this study, we demonstrate the constitutive, endothelial cell-specific expression of EPCR in vivo. Abundant expression was particularly detected in the aorta and large arteries. In vitro cultured, arterial endothelial cells were also found to express abundant EPCR and were capable of promoting significant levels of protein C activation. EPCR was found to greatly accelerate protein C activation by examining functional activity in transfected cell lines expressing EPCR and/or TM. EPCR decreased the dissociation constant and increased the maximum velocity for protein C activation mediated by the thrombin-TM complex. By these mechanisms, EPCR appears to enable significant levels of protein C activation in large vessels. These results suggest that the protein C anticoagulation pathway is important for the regulation of blood coagulation not only in microvessels but also in large vessels.