Metastasis involves several distinct steps, including one in which the tumor cell, after entry into the bloodstream, comes to rest in a capillary located at the distant site where a metastatic tumor will ultimately form. Components of the blood-clotting pathway may contribute to metastasis by trapping cells in capillaries or by facilitating adherence of cells to capillary walls. Conceivably, anticoagulants could interfere with this step in the metastatic process. In this review, we have summarized current knowledge on the interaction of malignant cells, clotting factors, and anticoagulants. We used computerized (MEDLINE) and manual searches to identify studies done in humans, in animals, and in in vitro systems that were published in English between 1952 and 1998. We found many reports that the formation of metastatic tumors could be inhibited by heparin, a vitamin K antagonist (warfarin), and inhibitors of platelet aggregation (prostacyclin and dipyridamole). Despite these encouraging preliminary results and a compelling biochemical rationale, only limited information exists on the clinical use of anticoagulants for the prevention or treatment of metastatic cancer because there have been so few controlled and prospectively randomized studies on this topic. In view of the preliminary results, anticoagulants may hold promise for the prevention and treatment of metastases. We believe that larger controlled investigations are strongly warranted to evaluate the clinical potential of anticoagulants for the prevention and treatment of metastases in humans.

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Inhibition of Metastases by Anticoagulants

Prostaglandin (PG) and thromboxane (TX) production by homogenates of human intracranial tumors (33 gliomas, 32 meningiomas, six brain metastases) and "normal" brain (n = 26) from tumor-bearing patients was studied. PGF2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha (the hydrolysis product of PGI2) and TXB2 (the hydrolysis product of TXA2) were determined by high-resolution gas chromatography-mass spectrometry after ex vivo metabolism of endogenous arachidonic acid. Prostanoid profiles (relative abundance of each metabolite) were different for gliomas and meningiomas, but similar for gliomas and their nontumoral counterpart, i.e., "normal" brain. Mean overall prostanoid production was significantly higher in gliomas (539 +/- 95) and meningiomas (523 +/- 69) than in "normal" brain (198 +/- 23). Prostanoid synthesis significantly increased with anaplastic grade (glioblastomas greater than anaplastic astrocytomas greater than slow-growing astrocytomas greater than "normal" brain), while profiles did not substantially change (TXB2 was the most and 6-keto-PGF1 alpha the least abundant product). Meningioma profiles showed no marked prevalence of any particular metabolite and no major differences between histological subgroups. All brain metastases from different carcinomas (n = 5) showed a prevalence of TXB2 and PGE2 and very low PGD2 synthesis.

https://cancerres.aacrjournals.org/content/canres/49/6/1505.full.pdf

Prostaglandin and Thromboxane Synthesis by Human Intracranial Tumors

✓ In vitro drug sensitivity assays have been developed with the goal of predicting the clinical response to chemotherapy. The colony-forming assay, radiolabeled precursor inhibition assay, and microcytotoxicity assay are most commonly used. In retrospective studies, the assays correctly predict clinical response to a chemotherapeutic agent in 50% to 70% of patients and predict clinical resistance in nearly 100% of patients. All of the assays suffer from technical and theoretical problems. In vitro assays depend on cell culture and therefore do not entirely simulate in vivo conditions. Heterogeneity in chemosensitivity is commonly found and can complicate the interpretation of results. Further investigation is needed to determine if these assays will be able to select prospective chemotherapy for patients. The malignant origin of the cells in culture must be verified if meaningful conclusions are to be made.

In vitro drug sensitivity testing in human gliomas

Which T cells cause graft rejection

Fatty acids (FAs) have long been recognized for their nutritional value in the absence of glucose, and as necessary components of cell membranes. However, FAs have other effects on cells that may be less familiar. Polyunsaturated FAs of dietary origin (n-6 and n-3) cannot be synthesized by mammals, and are termed ‘essential’ because they are required for the optimal biologic function of specialized cells and tissues. However, they do not appear to be necessary for normal growth and metabolism of a variety of cells in culture. The essential fatty acids (EFAs) have received increased attention in recent years due to their presumed involvement in cardiovascular disorders and in cancers of the breast, pancreas, colon and prostate. Many in vitro systems have emerged which either examine the role of EFAs in human disease directly, or utilize EFAs to mimic the in vivo cellular environment. The effects of EFAs on cells are both direct and indirect. As components of membrane phospholipids, and due to their varying structural and physical properties, EFAs can alter membrane fluidity, at least in the local environment, and affect any process that is mediated via the membrane. EFAs containing 20 carbons and at least three double bonds can be enzymatically converted to eicosanoid hormones, which play important roles in a variety of physiological and pathological processes. Alternatively, EFAs released into cells from phospholipids can act as second messengers that activate protein kinase C. Furthermore, susceptibility to oxidative damage increases with the degree of unsaturation, a complication that merits consideration because lipid peroxidation can lead to a variety of substances with toxic and mutagenic properties. The effects of EFAs on cultured cells are illustrated using the responses of normal and tumor human mammary epithelial cells. A thorough evaluation of EFA effects on commercially important cells could be used to advantage in the biotechnology industry by identifying EFA supplements that lead to improved cell growth and/or productivity.

Diverse effects of essential (n-6 and n-3) fatty acids on cultured cells.

The effects of prostaglandin D2 (PGD2) on the growth of mouse malignant glioma cells were studied in vitro and in vivo. The in vitro studies consisted of various concentrations of prostaglandins (PG's) being added to cultures of mouse glioma cells. At concentrations above 2.5 micrograms/ml, PGD2 strongly inhibited the proliferation of glioma cells, whereas PGE2 had no effect at the same value. Exposure to 5.0 micrograms/ml PGD2 for more than 2 hours resulted in inhibition of glioma cell proliferation. This growth-inhibitory effect of PGD2 was related to the inhibition of DNA synthesis of the cells. The in vivo studies were performed with a subcutaneously transplanted mouse glioma model. Injection of 0.5 mg/kg PGD2 into the tumor was more effective than the same concentration given by intraperitoneal injection. In mice with intracranially transplanted glioma, daily intraperitoneal injection of 0.5 mg/kg PGD2 had no significant effect on survival time.

Growth-inhibitory effect of prostaglandin D2 on mouse glioma cells

/pdf/immunological-response-in-the-mouse-brain-ii-experimental-1az4vibbas.pdf

Immunological response in the mouse brain: II. Experimental immunotherapy model against transplanted mouse lymphoma in the brain.

Immunological response in the mouse brain: I. Transplantation immunity to mouse lymphoma graft.

行政の政策や接客業のサービスの質を向上させるためには，市民によるフィードバックの収集/分析と同時に都市の特徴を明らかにするための他の都市との比較が重要となる．しかし，都市によって政策やサービスは異なり，市民の抱える意見も異なるため，機械学習により複数の都市に適応した市民意見の分析を実現することは難しい．本論文では，都市を横断して市民意見を抽出する手法を提案する．実験では，横浜市民，札幌市民，仙台市民のつぶやきを対象として，特定の都市のつぶやきでファインチューニングしたモデルを，評価対象の都市の比較的少量のつぶやきを用いて再度ファインチューニングする手法の有効性を確認した．この際，評価対象の都市の訓練データは，異なる都市のつぶやきで訓練したモデルによる予測の確信度が高いものを選定することが有効であることを明らかにした． 

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Atsushi Keyaki

Papers

Growth-inhibitory effect of prostaglandin D2 on mouse glioma cells

Immunological response in the mouse brain: II. Experimental immunotherapy model against transplanted mouse lymphoma in the brain.

Immunological response in the mouse brain: I. Transplantation immunity to mouse lymphoma graft.

都市を横断した市民意見抽出の評価