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To dissect the role of endoplasmic reticulum (ER) stress and unfolded protein response in brain ischemia, we investigated the relevance of activating transcription factor 6α (ATF6α), a master transcriptional factor in the unfolded protein response, after permanent middle cerebral artery occlusion (MCAO) in mice. Enhanced expression of glucose-regulated protein78, a downstream molecular chaperone of ATF6α, was observed in both neurons and glia in the peri-infarct region of wild-type mice after MCAO. Analysis using wild-type and Atf6α−/− mice revealed a larger infarct volume and increased cell death in the peri-ischemic region of Atf6α−/− mice 5 days after MCAO. These phenotypes in Atf6α−/− mice were associated with reduced levels of astroglial activation/glial scar formation, and a spread of tissue damage into the non-infarct area. Further analysis in mice and cultured astrocytes revealed that signal transducer and activator of transcription 3 (STAT3)-glial fibrillary acidic protein signaling were diminished in Atf6α−/− astrocytes. A chemical chaperone, 4-phenylbutyrate, restored STAT3-glial fibrillary acidic protein signaling, while ER stressors, such as tunicamycin and thapsigargin, almost completely abolished signaling in cultured astrocytes. Furthermore, ER stress-induced deactivation of STAT3 was mediated, at least in part, by the ER stress-responsive tyrosine phosphatase, TC-PTP/PTPN2. These results suggest that ER stress plays critical roles in determining the level of astroglial activation and neuronal survival after brain ischemia. We here suggest a mechanism triggered after brain ischemia in which the enhanced level of endoplasmic reticulum (ER) stress—caused by deletion of the activating transcription factor ATF6α—leads to suppression of the STAT3-GFAP signaling, inhibition of astroglial activation/glial scar formation, and enhanced level of neuronal death in the peri-ischemic area. This is mediated, at least in part, through the ER stress-responsive tyrosine phosphatase, TC-PTP. CNTF, ciliary neurotrophic factor; GFAP, Glial fibrillary acidic protein; IL-6, interleukin 6; LIF, leukemia inhibitory factor; STAT3, signal transducer, and activator of transcription 3.

Pancreatic cancer has one of the poorest prognoses among malignant diseases. To understand its molecular mechanisms, we studied allelic losses on the long arm of chromosome 6. Using 55 paired DNAs of tumors and their corresponding normal tissues and 30 microsatellite markers that spanned the entire 6q chromosome arm, we found three distinct regions of common allelic loss: region A, a less than 500-kb region bordered by D6S449 and D6S283 on 6q21 with a loss of heterozygosity (LOH) frequency of 69% (38/55); region B, a 7-cM region bordered by D6S292 and D6S308 on 6q23-q24 with a LOH frequency of 60% (33/55); and region C, a 13-cM region bordered by D6S305 and D6S264 with a LOH frequency of 51% (28/55). We further focused on region A and constructed a physical map using yeast artificial chromosome (YAC) clones, their derived cosmid clones, and bacterial artificial chromosome (BAC) clones. Region A was completely covered by three overlapping BAC clones. Our results in the present study should shed light on the cloning and characterization of tumor suppressor genes in pancreatic carcinogenesis.

In human endometrial cancer, we have previously identified a 790-kb region of common allelic loss in chromosome bands 10q25-q26, flanked by D10S587 and D10S1723. We constructed a contig covering the entire deleted region using YACs, PACs, and BACs. Five overlapping cosmid clones derived from YAC clones completely covered the entire deleted region: its size was estimated to be no larger than 200 kb. We further performed two-color fluorescence in situ hybridization (FISH) analysis to confirm the deletion and narrowed down the deleted region to 100 kb or less; it was covered by three overlapping cosmid clones that were included in one BAC clone. Restriction endonuclease mapping identified a region in which NotI, SalI, SmaI, and Xhol were clustered, suggesting the possible existence of a CpG island.

N. Peters, R. Wellenreuther, B. Rollbrocker, Y. Hayashi, B. Meyer-Puttlitz, E-M. Duerr, D. Lenartz, D.J. Marsh, J. Schramm, O.D. Wiestler, R. Parsons, C. Eng & A. von Deimling (1998) Neuropathology and Applied Neurobiology24, 3–8 Analysis of the PTEN gene in human meningiomas Previous observations demonstrated that the neurofibromatosis type 2 gene (NF2) plays an important role in the pathogenesis of the transitional, fibroblastic and malignant variants of human meningiomas. No specific genes have been associated with the pathogenesis of meningothelial meningiomas and with the progression to anaplastic meningiomas. However, allelic losses on chromosomal arms 1p, 10q and 14q have been implicated in the process of malignant progression. Recently, PTEN (phosphatase and tensin homolog deleted on chromosome ten) also termed MMAC1 (mutated in multiple advanced cancers 1) or TEP1 (TGF—regulated and epithelial cell-enriched phosphatase), emerged as a candidate gene on chromosome 10q23.3. Initial studies revealed mutations of PTEN in limited series of glioblastomas, breast, kidney and prostate carcinomas mainly as cell lines. In order to evaluate the involvement of PTEN in the development of meningiomas, we have analysed the entire coding sequence of the gene in a series of 55 meningiomas (WHO grade I), 10 atypical meningiomas (WHO grade II) and 10 anaplastic meningiomas (WHO grade III). No PTEN mutations were seen in the WHO grade I meningiomas. However, one of the anaplastic meningiomas carried a somatic mutation. In addition, all tumours were examined for the presence of homozygous deletions of PTEN but these were not detected in any of the meningiomas. Our data suggest that mutations in PTEN are not involved in the formation of low grade meningiomas, but may contribute to malignant progression in a fraction of anaplastic meningiomas.

To disclose the relationship between tea consumption and lung cancer risk, we analyzed the data from a case-control study conducted in Okinawa, Japan from 1988 to 1991. The analysis, based on 333 cases and 666 age-, sex- and residence-matched controls, provided the following major findings. (a) The greater the intake of Okinawa tea (a partially fermented tea), the smaller the risk, particularly in women. For females, the odds ratios (and 95% confidence intervals) for those who consumed 1-4, 5-9, and 10 cups or more of Okinawan tea every day, relative to non-daily tea drinkers, were 0.77 (0.28-2.13), 0.77 (0.26-2.25) and 0.38 (0.12-1.18), respectively (trend: P = 0.032). The corresponding odds ratios for males were 0.85 (0.45-1.55), 0.85 (0.45-1.56) and 0.57 (0.31-1.06) (trend: P = 0.053). (b) The risk reduction by Okinawan tea consumption was detected mainly in squamous cell carcinoma. Daily tea consumption significantly decreased the risk of squamous cell carcinoma in males and females, the odds ratios being 0.50 (95% confidence interval 0.27-0.93) and 0.08 (0.01-0.68), respectively. These findings suggest a protective effect of tea consumption against lung cancer in humans.

Tumescenamide C, a new cyclic lipodepsipeptide, was isolated from a culture broth of an actinomycete Streptomyces sp. KUSC_F05. Tumescenamide C was a congener of tumescenamides A and B, representing a sixteen-membered ring system, consisting of two proteinogenic and three non-proteinogenic amino acids, to which a methyl-branched fatty acid was attached. The planar structure was determined by spectroscopic analysis, while its absolute stereochemistry was determined by chemical degradation and asymmetric synthesis. Tumescenamide C exhibited antimicrobial activity with high selectivity against Streptomyces species.

To clarify co-carcinogenic effects of chrysotile (Chry) and amosite (Amo) asbestos with benzo(a)pyrene (Bap), 0.2 mg UICC (International Union against Cancer) standard reference sample of asbestos and 0.4 mg Bap were applied intratracheally once a week for 6 weeks. Eighteen and 24 months after the last instillation the number of tumors was examined. The Chry + Bap group yielded 37 tumors including 16 carcinomas in 12 animals, and the Amo + Bap group yielded 30 tumors including 11 carcinomas in 12 animals. Tumor-bearing animals were 100% in the Chry + Bap group and 92% in the Amo + Bap group, and carcinoma-bearing animals were 83% and 67%, respectively. The animals injected with Chry, Amo, and Bap alone developed no tumors. The number of tumors and carcinomas and the frequency of the tumor- or carcinoma-bearing animals in Chry + Bap and Amo + Bap were significantly higher than those of the groups injected independently. The number of tumors or the frequency of tumor-bearing animals was higher in Chry + Bap than in Amo + Bap; however, these differences were not significant. These results indicate that both Chry and Amo play an important role in the genesis of bronchogenic carcinoma.

To clarify whether serpentine and amphibole asbestos have different effects on the lung, UICC chrysotile and amosite asbestos were injected intratracheally into hamster lung, and the lungs were examined at 30 min, 1,4,8, and 24 h, and 2 and 4 days after asbestos application by light and scanning electron microscopy. A leukocyte and macrophage reaction appeared at 4 h and increased up to 2 days, and the cell reaction was stronger and more prolonged after application of chrysotile than after application of amosite asbestos. Furthermore, chrysotile induced more prominent cell (leukocytes or/and macrophages) necrosis and alveolar wall thickening. These findings indicate that chrysotile asbestos induces more stronger cell reactions in the alveolar wall, and is more noxious than amosite. Acta Pathol Jpn 42: 707–711, 1992.

A 39-year-old male was admitted complaining of nonproductive cough and dyspnea on exertion. Death occurred eight months after onset of the symptoms. Autopsy examination showed that the pulmonary trunk and left main pulmonary artery were markedly dilated and completely occluded by a tumor. The tumor had infiltrated into the left upper lobe and mediastinal lymph nodes, and metastatic nodules were found in both lungs and in the left adrenal gland. Small foci of infarction were noted in the lower lobes of both lungs. The tumor cells were of two types; pleomorphic spindle cells and bizarre multinucleated giant cells. Immunohistochemically, they were positive for vimentin, myosin, and lysozyme, but negative for desmin and muscle-specific actin. The cytoplasm of the tumor cells was showed by electron microscopy to contain microfilaments, dense bodies, and pinocytotic vesicles. We diagnosed this case as undifferentiated sarcoma of the pulmonary artery. Approximately 100 cases of pulmonary artery sarcoma have been reported. Histopathologically, almost all of the reported cases showed both spindle cells and pleomorphic giant cells, indicating a biologically anaplastic neoplasm.

Ferruginous bodies were extracted quantitatively from 508 patients; operated 242 with lung cancer and 94 with non-lung cancer, and autopsy 51 from hepatomas, 42 from stomach cancers, and 79 from non-cancer diseases. The bodies were divided morphologically into 4 types; 2 types may be from asbestos and the other 2 types from carbon and silicate which were very rarely found. The incidence of the bodies was the highest in hepatoma 96.8, followed by lung cancer 90.8%, non-lung cancer 80%, stomach cancer 76.2%, and non-cancer 74.2% in the years 1975-1981. Distribution of count of asbestos bodies was characteristic in patients with lung cancer, i.e. the cases who had asbestos bodies above 100/5 g of wet lung were found in 36 of 242 patients with lung cancer (14.8%) who were all smokers and 15 of 266 patients with the other diseases (5.6%) with significant difference between the two groups. Moreover, out of 14 patients who had the bodies above 300/5 g of wet lung, 9 were patients with lung cancer and also smoked heavily, and remaining 5 patients with diseases other than lung cancer consisted of 2 heavy smokers, a moderate and a mild smoker, and a non-smoker. These evidences may suggest the existence of some relation between occurrence of lung cancer and low degree of asbestos exposure with addition of smoking.

Epidemiological reports indicate that occupational asbestos exposure and smoking habit make increase the incidence of lung carcinomas greatly. To elucidate the synergetic effect of smoking and asbestos exposure, hamsters were injected intratracheally with asbestos and benzo(a)pyrene(Bap), which is contained in cigarette smoke, singly or in combination. Tumor was not induced in the hamsters injected with asbestos or Bap alone except epithelial hyperplasia. On the other hand, 7 tumors out of 34 animals were found in groups injected with both asbestos and Bap from 12 months to 19 months after injection. Two of them were carcinomas. This result seemed to indicate synergetic effect of asbestos and Bap in causing carcinoma of the lung.