Histological sequence of the development of rat mesothelioma by MWCNT,with the involvement of apolipoproteins

A rat model of mesothelioma development by peritoneal injection of multiwalled carbon nanotube (MWCNT) has been established and found to be useful to understand the mechanisms underlying fibrous particles-associated carcinogenesis. Its detailed histological sequence, however, remains largely obscure. We therefore aimed to assess the time-course of mesothelioma development by MWCNT and evaluate a set of lipoprotein-related molecules as potential mechanism-based biomarkers for the phenomenon. Male Fischer 344 rats were injected intraperitoneally (ip) with MWCNT (MWNT-7) at 1 mg/kg body weight, and necropsied at 8, 16, 24, 32, or 42 wk after injection. For biochemical analyses of the lipoprotein-related molecules, more samples, including severe mesothelioma cases, were obtained from 2 other carcinogenicity tests. Histologically, in association with chronic inflammation, mesothelial proliferative lesions appeared at c. Wk-24. Before and at the beginning of the tumor development, a prominent infiltration of CD163-positive cells was seen near mesothelial cells. The histological pattern of early mesothelioma was not a papillary structure, but was a characteristic structure with a spherical appearance, composed of the mesothelioma cells in the surface area that were underlain by connective tissue-like cells. Along with the progression, mesotheliomas started to show versatile histological subtypes. Serum levels of apolipoprotein A-I and A-IV, and a ratio of HDL cholesterol to total cholesterol were inversely correlated with mesothelioma severity. Overall, the detailed histological sequence of mesotheliomagenesis by MWCNT is demonstrated, and indicated that the altered profile of apolipoproteins may be involved in its underlying mechanisms.     

Case report of intralobar pulmonary sequestration detected by lung cancer screening with low-dose spiral CT

A 52-year-old man underwent lung cancer screening with low-dose spiral computed tomography (CT) in a medical check-up at the Japanese Red Cross Kumamoto Health Care Center. He was asymptomatic. Chest x-ray on a medical check-up showed no abnormal shadows. CT scans revealed a nodule in the right lower lung, suggestive of its connection to the descending thoracic aorta. A diagnosis of pulmonary sequestration was considered. He was transferred to Kumamoto University Hospital for further examination. Contrast enhanced multidetector CT images demonstrated that a nodule in the right lower lobe and an anomalous artery ran from the descending thoracic aorta, flowed through the right lower lobe and returned to the right inferior pulmonary vein. Intralobar pulmonary sequestration was confirmed by contrast enhanced multidetector CT. We report this case of asymptomatic intralobar pulmonary sequestration diagnosed using contrast enhanced multidetector CT.     

A case of atypical type A thymoma with vascular invasion and lung metastasis

We present a case of type A thymoma with invasion of the left brachiocephalic vein and lung metastases. An 84-year-old man underwent extended thymectomy combined with left brachiocephalic vein reconstruction and resection of a lung metastasis. Histological examination showed vascular invasion by the tumor. The lung metastasis had high mitotic activity and slight nuclear enlargement, the so-called “atypical” features, but the main part of the primary tumor did not. However, the intravascular portion of the tumor had “atypical” histological features like the lung metastasis. It seems that “atypical” histological features are related to clinically malignant behavior.     

RANKL-induced DC-STAMP is essential for osteoclastogenesis

Osteoclasts are bone-resorbing, multinucleated giant cells that are essential for bone remodeling and are formed through cell fusion of mononuclear precursor cells. Although receptor activator of nuclear factor-kappaB ligand (RANKL) has been demonstrated to be an important osteoclastogenic cytokine, the cell surface molecules involved in osteoclastogenesis are mostly unknown. Here, we report that the seven-transmembrane receptor-like molecule, dendritic cell-specific transmembrane protein (DC-STAMP) is involved in osteoclastogenesis. Expression of DC-STAMP is rapidly induced in osteoclast precursor cells by RANKL and other osteoclastogenic stimulations. Targeted inhibition of DC-STAMP by small interfering RNAs and specific antibody markedly suppressed the formation of multinucleated osteoclast-like cells. Overexpression of DC-STAMP enhanced osteoclastogenesis in the presence of RANKL. Furthermore, DC-STAMP directly induced the expression of the osteoclast marker tartrate-resistant acid phosphatase. These data demonstrate for the first time that DC-STAMP has an essential role in osteoclastogenesis.     

Mechanism of action and selective toxicity of ascamycin, a nucleoside antibiotic.

An unidentified Streptomyces sp. produces two nucleoside antibiotics, ascamycin and its dealanyl derivative. In contrast to the broad antibacterial activity of dealanylascamycin against various gram-negative and gram-positive bacteria, ascamycin showed selective toxicity against Xanthomonas citri and X. oryzae. Both ascamycin and dealanylascamycin inhibited the protein synthesis of X. citri, but only dealanylascamycin inhibited that of Escherichia coli. In cell-free systems from E. coli and X. citri, both antibiotics, at ca. 0.04 micrograms/ml, inhibited the polyuridylate-directed synthesis of polyphenylalanine by ca. 50%. These data suggest that ascamycin cannot permeate the bacterial membrane. The dealanylating activity toward ascamycin was found only on the cell surface of bacteria susceptible to ascamycin. Dealanylascamycin must then have been transported into cytoplasm, where it inhibited protein synthesis.     

Portal-systemic shunt through the right renal vein developing following portal tumor thrombus

Despite the semi-routine use of color Doppler sonography for evaluating portal circulation abnormalities, there is a relative paucity of information on portal-systemic (P-S) shunt through the right renal vein (P-SR shunt). We report such a case. The patient was a 60-year-old woman with hepatocellular carcinoma on liver cirrhosis. Serial sonography showed an aggravation in findings; an increase in the size of the tumor was followed by formation of a portal tumor thrombus, and then occurrence of a P-SR shunt. We present this case, with a comparison between the patient's clinical course and the color Doppler results. To our knowledge, this is the first report to make such a comparison in a P-SR shunt case. We also briefly review the literature.     

Vitamin K<Subscript>2</Subscript> selectively induced apoptosis in ovarian TYK-nu and pancreatic MIA PaCa-2 cells out of eight solid tumor cell lines through a mechanism different from geranylgeraniol

PURPOSE: In this study, we examined the effects of vitamin K(2) (menaquinone 4), which has a geranylgeranyl side chain, on various lines of cells derived from human solid tumors and compared them with the effects of geranylgeraniol (GGO). METHODS: Cell proliferation was determined with 3'-[1-[(phenylamino)carbonyl]-3,4-tetrazolium- bis (4-methoxy-6-nitro) benzene-sulfonic acid hydrate (XTT), and the induction of apoptosis was analyzed by TUNEL staining and flow cytometry as well as by measurement of DNA fragmentation, released nucleosomes and caspase-3 activity. Levels of Bcl-2, Bax and cytochrome c were determined by immunoblotting. RESULTS: GGO inhibited the growth of all eight cell lines derived from solid tumors, while vitamin K(2) selectively inhibited the proliferation of ovarian TYK-nu and pancreatic MIA PaCa-2 cancer cells, inducing apoptosis in both cell lines. Far more time was required for the induction of apoptosis in these two cell lines by vitamin K(2) than by GGO. Apoptotic signals induced in TYK-nu cells during the first 2 days that followed the addition of vitamin K(2) to the culture medium were reversible, but these signals became irreversible after 3 days of treatment with vitamin K(2). The induction of apoptosis in TYK-nu cells by vitamin K(2) was inhibited by cycloheximide and also by starvation at a low concentration of serum. Neither cycloheximide nor starvation had any effect on the induction of apoptosis by GGO. Cytochrome c was released simultaneously with the initiation of apoptosis on treatment of TYK-nu cells with vitamin K(2) or GGO. However, GGO induced the release of cytochrome c from isolated mitochondria, while vitamin K(2) did not. The amount of Bcl-2 in TYK-nu cells was reduced by vitamin K(2), but not by GGO. CONCLUSIONS: In contrast to GGO, vitamin K(2) induced apoptosis selectively in pancreatic MIA-PaCa 2 and ovarian TYK-nu cancer cells. It is suggested that de novo protein synthesis might be necessary for induction of apoptosis by vitamin K(2) but not by GGO, and thus, that vitamin K(2) and GGO might induce apoptosis by different mechanisms.     

Current status of development of anticancer agents in Japan

To investigate the current status of the development of anticancer agents in Japan, we examined the number of these agents developed after 1999, their target diseases, and the association between the number of approved agents and the number of patients with the diseases. The data were obtained via the Internet. Of the 487 agents approved from 1999 to April 2007, 84 were anticancer drugs. Of these 84, 46 were approved based on clinical trials and 38 were approved through the new drug application for off-label usages without clinical trials. The target diseases of the 46 agents approved through clinical trials were nonhematologic tumors in 29, hematologic malignancies in 13, and others in 4. Of the 38 approved through the new drug application for off-label usages, 31 were for nonhematologic tumors and 7 for hematologic malignancies. The number of approved anticancer agents for hematologic malignancies per unit patient population was 6.5-times as many as that for nonhematologic tumors. This study demonstrated that the situation regarding the development of anticancer agents differs among tumor types. The majority of anticancer agents developed target hematologic malignancies, while the newly developed anticancer agents have affected treatment strategies for solid tumors.