Background and Purpose-Despite technical advances in endovascular and microsurgical treatment, patients with aneurysmal subarachnoid hemorrhage still have a high mortality and morbidity rate. To improve the treatment results in patients with aneurysms, we must better understand the pathophysiology of cerebral aneurysms and the mechanisms leading to their rupture. Therefore, we studied the pathological differences between unruptured and ruptured aneurysms. Methods-Ruptured (nϭ44) and unruptured (nϭ27) aneurysms were obtained at surgery. The aneurysmal endothelium was scored from 0 (normal) to 5 (complete disruption) by using a scanning electron microscope. The aneurysmal wall was evaluated by immunohistochemical methods. The wall structure was scored from 1 (dense collagen and rich, smooth muscle cells) to 5 (hyaline-like structure). The degree of inflammatory cell invasion into the wall was also scored from 0 (very few cells) to 3 (many cells). Results-Ruptured aneurysms manifested significant endothelial damage (score of 3.7 versus 0.8; Mann-Whitney U test, PϽ10 Ϫ3 ), significant structural changes of the wall (3.7 versus 1.7, PϽ10 Ϫ5 ), and significant inflammatory cell invasion (2.2 versus 0.8, PϽ10

Background and Purpose: The relation between serum total cholesterol levels and stroke is controversial. The Akita Pathology Study provides data on the association of serum total cholesterol, different types of stroke, and distribution of stenosis in cerebral arteries.Methods: The data are based on 750 autopsied men aged 30 years and older who were admitted to a local hospital in northeast Japan between 1966 and 1984. The overall autopsy rate was 88%. The grade of

An analysis was performed of 2,168 consecutive stroke patients who were examined by computed tomography and entered into a hospital-based stroke registry in Akita Prefecture, Japan. The occurrence of cerebral hemorrhage, cerebral infarction, and subarachnoid hemorrhage was 30, 55, and 14%, respectively. Age-specific rates of subarachnoid hemorrhage were higher in women than men; other types of stroke showed a preponderance in men. Total strokes increased in the winter; this seasonal difference was confined to cerebral hemorrhage. Putaminal hemorrhages predominated in the younger age groups; thalamic hemorrhage and cerebellar hemorrhage were predominant in the older age groups. The increased accuracy of the diagnosis of stroke subtypes by the use of computed tomography in this study is in contrast to other community-based epldemiologic studies that have relied solely on clinical diagnosis. This increased accuracy is seen to be the reason that new ratios of stroke subtype incidence have been identified. (Stroke 1987;18:402-406) T HE World Health Organization coordinated a collaborative study of stroke incidence in 17 centers from developing and developed countries between 1971 and 1974.' The Japanese centers participating were found to have the highest age-adjusted stroke incidence rates of the 17 centers in the study. Among all these centers, Akita, Japan showed the highest incidence rate for stroke. In epidemiologic studies, diagnosis of stroke is usually based on clinical judgment. The accuracy of clinical diagnoses is known to be rather high, 23 but misdiagnosis can reach 20-30% 4 in pathologic subtypes of stroke (i.e., cerebral hemorrhage, cerebral infarction, and subarachnoid hemorrhage, SAH). Because misdiagnosis of subtypes distorts the results in epidemiologic studies of stroke and because computed tomography (CT) provides highly accurate diagnoses, 5 the Akita medical community has confirmed most stroke patients in recent years by CT, and since 1983 has set up a hospitalbased stroke registry of patients confirmed by CT. This paper analyzes the diagnoses in the stroke registry in Akita and compares them with the results of previous community-based epidemiologic studies of the subtypes of stroke. Subjects and MethodsAll strokes diagnosed by CT from November 1, 1983 to May 31, 1985 were included in the present study. Twenty-four hospitals, encompassing all instiFrom the doctors group of clinico-epidemiological study for stroke, Akita.Address for reprints: Kazuo Suzuki, MD, Department of Epidemiology, Research Institute of Brain and Blood Vessels-Akita, 6-10, Senshu-Kubota-Machi, Akita 010, Japan.Received May 15, 1986; accepted November 5, 1986. tutes using CT in Akita Prefecture, participated. Stroke was defined as the onset of rapidly developing clinical signs of focal or global disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than a vascular origin. Recurring attacks were included. All cases were examined using CT within 3 weeks of the onset...

Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial-mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44 CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44 CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44 non-CSCs into the undifferentiated CD44 CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.

Abstract. We developed a reliable new model system for assaying liver metastasis using NOD/SCID/γ c null (NOG) mice. Seven human pancreatic cancer cell lines were examined for their ability to form diverse metastatic foci in the livers of NOD/SCID and NOG mice. Capan-2 and PL45 showed no metastasis when seeded at up to 10 5 cells in both strains, and no BxPC-3 metastasis was observed in NOD/SCID mice. The NOD/SCID mouse model detected liver metastasis only in the AsPC-1 cell line when inoculated with >10 3 cells. In contrast, when inoculated with only 10 2 MIA PaCa-2, AsPC-1 and PANC-1 cells, liver metastasis was evident in 71.4% (5/7), 57.1% (4/7) and 37.5% (3/8) of the NOG mice, respectively. Capan-1 and BxPC-3 cells metastasized when seeded at 10 3 cells in 50% (5/10) and in 12.5% (1/8) of the mice, respectively. Using the NOG mouse model system, we established a highly metastatic cell line, liver metastasizedBxPC-3 (LM-BxPC-3), from liver metastatic foci formed by the relatively poorly metastatic parental BxPC-3 cell line. The gene expression profiles of parental and LM-BxPC-3 cells were compared, and we identified forty-five genes that were either upregulated or downregulated >4-fold in the LMBxPC-3 cell line. We validated 9 candidate protein-coding sequences, and examined the correlation between their expression pattern and the in vivo liver metastatic potential of all 7 pancreatic cancer cell lines. Only S100A4 expression correlated with the ability to form liver metastases, as evaluated in our quantitative model of metastasis in NOG mice. These results suggested that S100A4 is a key regulator of liver metastasis in pancreatic cancer, and demonstrated the feasibility of using the quantitative metastasis model to search for and develop new anti-cancer therapies and novel drugs against this and other key molecules.