Synthesis and antitumor activity of tropolone derivatives. 7. Bistropolones containing connecting methylene chains.

Bistropolone derivatives (4-12) containing differing lengths of linkage between the two tropolone rings were prepared and examined for their antitumor activity in in vitro (KB cell) and in vivo (leukemia P388 in mice) systems. Parent compound 3, related compounds previously prepared, and the new compounds 4-12 were evaluated for inhibitory activity against ribonucleotide reductase by indirect means to measure their effects on the dNTP pool imbalance. Present structure-activity relationship results would suggest that potently active bistropolones in vivo inhibit intracellular ribonucleotide reductase through chelating with the two irons at the two active sites of the enzyme.     

Lateral position prevents respiratory occlusion during surgical procedure under general anesthesia in the patient of huge anterior mediastinal lymphoblastic lymphoma

Lymphoblastic lymphoma, an aggressive mediastinal mass, is recognized as serious threat to the patient in developing cardiac tamponade or airway obstruction. Surgical procedure is often required to relieve clinical emergency and to establish prompt pathological diagnosis. However, in such a patient, acute respiratory occlusion in the spine position can be a life-threatening complication during general anesthesia. We describe a 17-year-old man whose cardiac tamponade was treated by pericardial-pleural window through a left anterior thoracotomy in the lateral position. The patient recovered from hemodynamic compromise without showing respiratory occlusion during general anesthesia and remained in the lateral position until extubation. Pathological diagnosis was precursor T-lymphoblastic lymphoma. There were no complications attributable to the operative procedure. Further chemotherapy reduced the mediastinal mass in size after two weeks when the patient developed sepsis and died. Lateral position prevents respiratory occlusion during surgical procedure under general anesthesia in the patient of huge anterior mediastinal tumor with airway obstruction.     

Germinoma with granulomatous reaction arising from the corona radiata; case report and review of articles]

We report a rare case of germinoma with granulomatous reaction arising from the corona radiata. This 20-year-old man was admitted to our hospital complaining of progressive motor weakness on the right side. CT demonstrated a poorly demarcated high density area in the left corona radiata, which was heterogeneously enhanced after administration of contrast medium. Moreover, the continuity of the mass to the ventricular wall was confirmed on MRI. At the first operation, subtotal removal of the tumor was performed through a fronto-parietal craniotomy. The diagnosis for the specific neoplasm was not established histologically, but granuloma caused by fungal infection was the most likely cause of the lesion. We tried amphotericin B (AmB), and remission of the tumor was obtained. However, during the following 3 months, the size of the tumor gradually enlarged again. AmB was repeatedly administered, but this time the treatment was ineffective. Six months later, on May 21, 1990, the second operation was performed and histological examination revealed typical germinoma consisting of two-cell pattern. Subsequently, the patient underwent focal irradiation of 33 Gy to the tumor site, and the tumor completely disappeared. As intracranial germinomas are observed to be successfully cured by radiotherapy and/or chemotherapy, choice of the therapeutic management must be carefully determined according to the histological diagnosis, especially in young people. A variety of locations of germinomas and the accompanying granulomatous reactions could create some diagnostic confusion, so great care must be taken in the treatment of much intracranial germinomas.     

Independent association of antibodies against human papillomavirus type 16 and E7 proteins with cervical cancer

The E4 open reading frame (ORF) of human papillomaviruses (HPVs) is transcribed in abundant mRNAs encoding an fusion gene during the productive infection, and the HPV 16 E7 ORF encodes an oncoprotein detectable in the cell lines derived from cervical carcinoma. We examined 421 human sera, which included 108 samples from the patients with cervical carcinoma, for the presence of IgG antibodies against the HPV 16 E4 and E7 proteins by enzyme-linked immunosorbent assay. Bacterially expressed fusion protein lac- and nonfusion protein E7 were purified and used as antigens. All of the 22 serum samples positive for anti-E7 antibody and the 11 out of 15 samples positive for anti- antibody were from the patients with cervical carcinoma, but only one sample was found to contain both anti- and anti-E7 antibodies. These findings show specific and independent association of these antibodies with cervical carcinoma.     

Fibrate for treatment of primary biliary cirrhosis

Recent studies of the effectiveness of ursodeoxycholic acid (UDCA) therapy in patients with primary biliary cirrhosis (PBC) reported that UDCA therapy did not necessarily stop the progression of liver fibrosis in all patients, even those with early stage PBC. Thus, there is a need for more effective treatments that could prevent asymptomatic PBC from progressing to the icteric stage. Bezafibrate is effective in approximately two-thirds of non-icteric patients who have not shown a complete response to UDCA. Serum bilirubin, aspartate aminotransferase and γ-guanosine 5'-triphosphate levelswere significantly lower in patients who responded to additional bezafibrate on univariate analysis. The putative mechanism by which bezafibrate acts in cholestasis is by increasing phospholipid output into bile, which forms micelles with the hydrophobic bile acid that reduces its toxicity.     

Approach through the temporal horn of the lateral ventricle for clipping of large dorsal type basilar bifurcation aneurysms

Summary The authors describe an approach through the temporal horn of the lateral ventricle which proved to be useful for clipping of a large dorsal type basilar bifurcation aneurysms. It facilitates the preservation of the perforating arteries behind the aneurysm, because it gives sufficient working space to move the aneurysm dome. Furthermore this approach avoids many of the disadvantages of other approaches, especially the risk of iatrogenic injuries of the Sylvian or Labe's vein.     

Characterization of adenosine deaminase (ADA)-negative B-lymphoblastoid cells cocultured with ADA-positive fibroblasts

Abstract: A cell line, BAD05, derived from B lymphocytes of an adenosine deaminase (ADA; EC 3,5,4,4)-deficient patient could not proliferate in a serum-free medium containing 100 μmol/l deoxyadenosine. When BAD05 was cultured with ADA-positive fibroblasts, the proliferation of BAD05 was improved. BAD05 cell density increased when the initially mixed ratio of fibroblasts/BAD05 was 1/10 or higher, but decreased when the ratio was 1/20 or lower. Deoxyadenosine concentrations in the medium and ATP and deoxyATP (dATP) levels in the BAD05 were measured after 4 hours of coculture at initial BAD05 cell densities of 1 × 10⁵and 1 × 10⁶cells/ml. Deoxyadenosine concentrations in the medium decreased as the density of fibroblasts increased. The dATP level decreased as the mixed ratio rose. The ratio of fibroblasts/BAD05 rather than the cell density of fibroblasts had a larger effect on the dATP levels in BAD05. Under our experimental conditions, ADA-negative cells proliferated well when the ratio of ADA-positive cells/ADA-negative cells was over 1/10.     

Gerstmann-Sträussler syndrome — A variant type: amyloid plaques and Alzheimer's neurofibrillary tangles in cerebral cortex

Summary This report presents a variant of Gerstmann-Sträussler syndrome (GSS). A 53-year-old female had developed slowly progressive dementia and atactic gait since the age of 45. No myoclonic jerks and periodic synchronous discharges were observed throughout the illness. The neuropathological study revealed that many amyloid plaques and widespread Alzheimer's neurofibrillary tangles (NFTs) appeared in the cerebral cortex. Characteristically, the plaques reacted with anti-prion protein and none of them reacted with anti- protein, and they were made of many components, including amyloid cores, macrophages laden with lipid granules and/or degenerated neurites. Neuropil threads were seen mainly in amyloid plaques. Moreover, plaques appeared which were confluent and laminar in arrangement in the fifth and sixth cortical layers and had a close relationship to the neuronal loss. There was no spongiform change in the cerebral cortex or cerebellum. The cerebellum was almost intact except for a few amyloid plaques. Ultrastructurally, some of the plaques simulated kuru plaques and others had many degenerated neurites possessing paired helical filaments and other accumulated organelles. GSS has been proposed to include cases with progressive ataxia, dementia and massive multifocal plaques in the brain with or without cerebral spongiform changes. The case presented here is a very peculiar case of GSS. Recently, similar cases have been reported in some large families, diagnosed as familial Alzheimer's disease. These cases may be a telencephalic form with numerous NFTs of GSS.     

Contribution of Asian mouse subspecies Mus musculus molossinus to genomic constitution of strain C57BL/6J, as defined by BAC-end sequence-SNP analysis

MSM/Ms is an inbred strain derived from the Japanese wild mouse, Mus musculus molossinus. It is believed that subspecies molossinus has contributed substantially to the genome constitution of common laboratory strains of mice, although the majority of their genome is derived from the west European M. m. domesticus. Information on the molossinus genome is thus essential not only for genetic studies involving molossinus but also for characterization of common laboratory strains. Here, we report the construction of an arrayed bacterial artificial chromosome (BAC) library from male MSM/Ms genomic DNA, covering approximately 1x genome equivalent. Both ends of 176,256 BAC clone inserts were sequenced, and 62,988 BAC-end sequence (BES) pairs were mapped onto the C57BL/6J genome (NCBI mouse Build 30), covering 2,228,164 kbp or 89% of the total genome. Taking advantage of the BES map data, we established a computer-based clone screening system. Comparison of the MSM/Ms and C57BL/6J sequences revealed 489,200 candidate single nucleotide polymorphisms (SNPs) in 51,137,941 bp sequenced. The overall nucleotide substitution rate was as high as 0.0096. The distribution of SNPs along the C57BL/6J genome was not uniform: The majority of the genome showed a high SNP rate, and only 5.2% of the genome showed an extremely low SNP rate (percentage identity = 0.9997); these sequences are likely derived from the molossinus genome.     

Immunological circumvention of multiple organ metastases of multidrug resistant human small cell lung cancer cells by mouse-human chimeric anti-ganglioside GM2 antibody KM966

The formation of metastases in multiple organs and acquired multi-drug resistance (MDR) are the major obstacles for treatment of human small-cell lung cancer (SCLC). To explore the possibility of immunological overcoming of multiple-organ metastases produced by refractory SCLC, we established the MDR variant (SBC-3/DOX), expressing P-glycoprotein, of parental SBC-3 cells by culturing with gradually increasing concentration of adriamycin. Both SBC-3 and SBC-3/DOX cells expressed a high amount of ganglioside GM2, an ideal target of SCLC cells. A mouse-human chimeric anti-GM2 monoclonal antibody (KM966) induced antibody-dependent cellular cytotoxicity (ADCC) mediated by human mononuclear cells (lymphocytes and monocytes) and complement-dependent cytotoxicity (CDC) mediated by human AB serum against SBC-3/DOX cells to a similar extent compared with parental SBC-3 cells. Pretreatment of human effector cells with various cytokines induced further enhancement of the KM966-dependent ADCC against SBC-3/DOX cells. Intravenous injection of SBC-3 or SBC-3/DOX cells into natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice developed metastases in multiple organs (liver, kidneys and lymph nodes). Interestingly, SBC-3/DOX cells produced metastases more rapidly than SBC-3 cells, suggesting more aggressive phenotype of SBC-3/DOX cells than their parental cells in vivo. Systemic treatment with KM966, given on days 2 and 7, drastically inhibited the formation of multiple-organ metastases produced by both SBC-3 and SBC-3/DOX cells, indicating that KM966 can eradicate metastasis by SCLC cells irrespective of MDR phenotype. These findings suggest that the mouse-human chimeric KM966 targets the GM2 antigen, and might be useful for the immunological circumvention of multiple-organ metastases of refractory SCLC. This revised version was published online in July 2006 with corrections to the Cover Date.