A pilot study of bortezomib in Korean patients with relapsed or refractory myeloma

Recent clinical trials showed that bortezomib, a novel proteasome inhibitor, had therapeutic activity in multiple myeloma. However, there was no data about the feasibility of bortezomib in Korean patients. We performed a pilot study of bortezomib in patients with relapsed or refractory myeloma (1.3 mg/m2 twice weekly for 2 week in a 3-week cycle). Seven patients were enrolled. The median age of patients was 59 yr. All patients previously received VAD (vincristine, doxorubicin and dexamethasone) and thalidomide chemotherapy. Three patients previously received alkylator-containing chemotherapy and 4 patients, autologous stem cell transplantation. Bortezomib monotherapy resulted in 3 partial remissions (43%), 3 no changes (43%) and 1 progressive disease (14%). One patient who had no response to bortezomib monotherapy experienced partial remission after addition of dexamethasone to bortezomib. The most common serious toxicity was thrombocytopenia (grade 3/4, 10 of 20 cycles (50%)) and grade 3 peripheral neuropathy was developed in 2 of 20 cycles (10%). Drug-related adverse event led to discontinuation of bortezomib in 1 patient. There was no treatment related mortality. Overall, bortezomib seems to be effective and feasible. Conduction of larger clinical studies on Korean patients is necessary to characterize clinical efficacy and safety of bortezomib more precisely.     

Differentiation processes of oval cells into hepatocytes: proposals based on morphological and phenotypical traits in carcinogen-treated hamster liver

Hepatic stem cells participate in the recovery process of liver with severe injury or impaired hepatocyte regeneration. Oval cells (an oval-shaped liver cell population newly emerging from the portal or periportal zones following severe hepatic cellular damage) are believed to be the progeny of liver stem cells and precursor cells of both hepatocytes and bile duct cells. An attempt was made to define the differentiation processes of hepatic oval cells into mature hepatocytes in hamsters fed a choline-deficient diet and treated with diethylnitrosamine and 2-acetyl aminofluorene, on the basis of histopathological, electron microscopical, histochemical and immunohistochemical characterization of hepatic cell components. Two putative differentiation pathways of oval cells toward mature hepatocytes are proposed, namely (1) the differentiation of ductular-like oval cells via ductular/acinar-type hepatocytes, and (2) the differentiation of individual oval cells via small hepatocytes. Those proposals were strongly supported by consistent immunoreactivity of the cells for OV-6, an oval cell marker, and differential expression patterns for CK19 and PAS-positive cytoplasmic glycogen granules.     

Cytokine responses in mice infected with<Emphasis Type="Italic"> Clonorchis sinensis</Emphasis>

FVB and BALB/c mice show different morbidity, development of Clonorchis sinensis, and pathological changes following C. sinensis infection. FVB mice are susceptible and BALB/c mice are relatively more resistant to C. sinensis infection. To investigate the relationship between cytokine reaction and susceptibility to C. sinensis infection in FVB and BALB/c mice, we described both the patterns and kinetics of Th1 cytokines and Th2 cytokines in spleen cell culture. Interleukin (IL)-4 and IL-10 cytokine production in the culture supernatants of the concanavalin-A-stimulated spleen cells increased at 2–3 weeks post-infection in both strains. IL-5 production increased between 2 and 5 weeks post-infection in both strains, and reached a peak level at 2 weeks post-infection in BALB/c mice and 4 weeks post-infection in FVB mice. In contrast, gamma interferon (IFN-) production decreased between 2 and 4 weeks in both strains. IL-2 production increased slightly in BALB/c mice following infection, but was unchanged in FVB mice. IL-4 production over preinfection levels was significantly higher in FVB mice, whereas IFN-, IL-2, and IL-10 production were significantly higher in BALB/c mice. The levels of serum immunoglobulin E (IgE) and blood eosinophils in both mouse strains significantly increased between 3 and 6 weeks postinfection. Serum IgE levels were significantly higher in FVB mice than in BALB/c mice. The results of this study suggest that susceptibility to C. sinensis infection is associated with Th2 cytokine production, especially IL-4 which is predominant in relatively susceptible FVB mice.     

Effect of ultraviolet light on the expression of adhesion molecules and T lymphocyte adhesion to human dermal microvascular endothelial cells

In order to determine the effect of ultraviolet radiation (UVR) on the cell adhesion molecules expressed in human dermal microvascular endothelial cells (HDMEC), the cells were exposed to varying UVR doses and the cell surface was examined for expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM- 1), and E-selectin. The effect of UVB irradiation on the binding of T lymphocytes to HDMEC was also examined. UVA irradiation did not affect the surface expression of ICAM-1, VCAM-1, or E-selectin on the HDMEC. However, following UVB exposure, ELISA demonstrated a significant increase in the baseline ICAM-1 cell surface expression on the HDMEC. However, no induction of either E-selectin or VCAM-1 was noted. UVB also significantly augmented ICAM-1 induction by IL-1alpha and TNF-alpha. VCAM-1 was induced by stimulating HDMEC with IL-1alpha following a UVB irradiation dose of 100 mJ/cm2. Flow cytometric analysis of the HDMEC stimulated with IL-1alpha for 24h demonstrated that 12% of the cells expressed VCAM-1 but either IL-1alpha or UVB irradiation alone failed to induce VCAM-1 expression. Enhancement of T cell-HDMEC binding by IL-1alpha or TNF-alpha treatment was not significantly affected after UVB irradiation. This study demonstrated that UVB irradiation can alter ICAM-1 and VCAM-1 expression on the HDMEC surface and that augmentation of ICAM-1 expression and the IL-1alpha-dependent induction of VCAM-1 following UVB exposure might be important steps in the pathogenesis of sunburn.     

Synthesis of 3-amino-ribofuranans having 1,5-α and -β structures by selective ring-opening polymerization of a 1,4-anhydro-3-azido-3-deoxy-α-D-ribopyranose derivative

Ring-opening polymerization of a new anhydro ribose-type monomer, 1,4-anhydro-3-azido-3-deoxy-2-O-tert-butyldimethylsilyl-α-D -ribopyranose (A3ASR), was investigated. The monomer was synthesized from 1,4-anhyro-α-D -xylopyranose by three steps comprising Walden inversion at the C3 position into ribose configuration. Ring-opening polymerization of A3ASR by Lewis acid catalysts such as boron trifluoride etherate and stannic chloride gave a stereoregular 3-azido-3-deoxy-2-O-tert-butyldimethylsilyl-(1→5)-α-D -ribofuranan having specific rotations of +246 ～ +271 deg · dm^?1 · g^?1 · cm³ and number-average molecular weights of 18,7 × 10³ ～ 25,1 × 10³. When the polymerization was carried out by antimony pentachloride at 0°C, the resulting polymer exhibited a negative specific rotation of ?6 deg · dm^?1 · g^?1 · cm³ and the C1 absorption in the ¹³C NMR spectrum shifted downfield to 107,5 ppm, suggesting that the polymer might consist of 1,5-β furanosidic unit. The reduction of the azido group of the 1,5-α and 1,5-β furanosidic polymers into amino group and subsequent desilylation gave 3-amino-3-deoxy-(1→5)-α- and -β-D -ribofuranans, respectively. In addition, copolymerization of A3ASR with 1,4-anhydro-2,3-di-O-tert-butyldimethylsilyl-α-D -ribopyranose (ADSR) in various feeds was performed by boron trifluoride etherate as catalyst to give copolymers with different monomeric components. The structural analysis of the homopolymers and copolymers was examined by means of ¹H and ¹³C NMR spectroscopies, IR spectroscopy, and optical rotation.     

Postnatal development of parvalbumin and calbindin D-28k immunoreactivities in the canine hippocampus

The calcium-binding proteins, parvalbumin and calbindin D-28k, are markers of different classes of GABAergic interneurons and display different functions. The present study was attempted to determine immunoreactivities and colocalization of the parvalbumin and calbindin D-28k in the developing canine hippocampus by immunohistochemistry. The calcium-binding protein-containing neurons showed different developmental patterns. The first appearance of parvalbumin immunoreactive nonpyramidal cells was observed at P7. Parvalbumin immunoreactivity was elicited by the sequence from CA3 to CA1 to reach an adult-like distribution pattern, which was reached at P60, while calbindin D-28k immunoreactivity appeared from P0, including pyramidal and nonpyramidal cells. The characteristic distribution of calbindin D-28k immunoreactive pyramidal cells was clarified by P28, and an adult-like distribution pattern was reached by the end of the second postnatal month. Double-labeled nonpyramidal cells were frequently seen in the subareas, CA3 of P14/CA1-CA2 of P28, where parvalbumin immunoreactive nonpyramidal cells were emerging. These data suggest that the colocalization of the two calcium-binding proteins during development is related closely to the area-specific maturation of parvalbumin expression, although either prenatal expression of calbindin D-28k or parvalbumin was not determined.     

Non-alcoholic duct-destructive chronic pancreatitis: recognition before definitive treatment

Non-alcoholic duct-destructive chronic pancreatitis is a new entity that differs morphologically and pathogenetically from alcoholic chronic pancreatitis. Some clinical and imaging features of this entity resemble those of pancreatic cancer, and hence most of the reported cases underwent pancreatic resections including an invasive pancreaticoduodenectomy. Recognition of this new entity before a definitive treatment is therefore important to avoid an unnecessary pancreatic resection. Recently, we experienced a case of non-alcoholic duct-destructive chronic pancreatitis in an 80-year-old man presenting with obstructive jaundice and whose radiologic features were characteristic as originally described. Recognition of this new entity before definitive treatment enabled us to manage this patient optimally. In addition, the relation between non-alcoholic duct-destructive chronic pancreatitis and chronic pancreatitis with diffuse irregular narrowing of the main pancreatic duct is discussed.     

Combined microcystic adnexal carcinoma and squamous cell carcinoma arising in the ovarian cystic teratoma--a brief case report.

Malignant transformation of mature cystic teratoma of the ovary can develop with an incidence of 1-2%. Squamous cell carcinoma is the most common malignant tumor arising in benign cystic teratoma. The authors have recently experienced a case of combined microcystic adnexal carcinoma and squamous cell carcinoma arising in a benign cystic teratoma of the ovary in a 72-year-old Korean woman. The right ovarian cystic mass had been ruptured and firmly adhered with salpinx and omental fat tissue on operation. Thickened cystic wall with yellowish white solid infiltrative lesion was noted grossly, and two different malignant tumors of microcystic adnexal carcinoma exhibiting both eccrine and hair follicular differentiation and squamous cell carcinoma were observed microscopically. PAS and CEA positivities suggested eccrine differentiation in areas of microcystic adnexal carcinoma.     

Virus-induced diabetes mellitus: VIII. Passage of encephalomyocarditis virus and severity of diabetes in susceptible and resistant strains of mice.

The diabetogenic capacity of the M-variant of encephalomyocarditis (EMC) virus was markedly diminished after passage in mouse kidney cell cultures. One passage in mice fully restored this capacity. Virus harvested after five passages in either susceptible (SWR/J) or resistant (C57BL/6J) strains of mice was capable of producing diabetes in susceptible SWR/J mice but not in resistant C57BL/6J mice. Resistance was not overcome by inoculating mice with high concentrations of virus. Immunofluorescence studies showed that islets from strains of mice (i.e. CBA, AKR, C57BL/6J, A/J) that did not develop diabetes after infection with EMC virus, nonetheless, contained virus antigens. The percentage of cells in the islets containing virus antigens varied from 3-6% in CBA to 13-5% in A/J. In contrast 38% of the islet cells in susceptible SWR/J mice contained virus antigens. It is concluded that both the genetic background of the host and the passage history of the virus influence the development of diabetes.