Association of L-type amino acid transporter 1 (LAT1) with the immune system and prognosis in invasive breast cancer

L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16–7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35–8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer

Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow

Mesenchymal stem cells (MSCs) are defined as cells that undergo sustained in vitro growth and can give rise to multiple mesenchymal lineages. Because MSCs have only been isolated from tissue in culture, the equivalent cells have not been identified in vivo and little is known about their physiological roles or even their exact tissue location. In this study, we used phenotypic, morphological, and functional criteria to identify and prospectively isolate a subset of MSCs (PDGFRα+Sca-1+CD45−TER119−) from adult mouse bone marrow. Individual MSCs generated colonies at a high frequency and could differentiate into hematopoietic niche cells, osteoblasts, and adipocytes after in vivo transplantation. Naive MSCs resided in the perivascular region in a quiescent state. This study provides the useful method needed to identify MSCs as defined in vivo entities

奄美諸島と八重山諸島における高齢者の生活と福祉ニーズ : 将来の生活の不安と生きがい感、食生活、保健医療・福祉サービス、地域の問題(2)

本研究の目的は、琉球弧の北に位世する鹿児島県の奄美諸励と南に位置する沖縄県の八重山諸島における島嘆地域の高齢者の生活の現状と福祉ニーズを把握することである。調査対象地は、奄美諸島の中心である奄美市(島嶼都市部)および瀬戸内町の加計呂麻島、請島、与路島(島嶼集落部)、八重山諸島の中心である石垣市(島嶼都市部)、竹富町西表島西部および鳩間島(島嶼集落部)であった。鹿児島県の場合、特に島嘆集落は過疎高齢化が進行し、集落機能の低下を余儀なくされている。沖細県の場合、鹿児島県ほどの過疎高齢化は進んでいない状況であるが、島嶼地域のもつ生活上の課題を共有している。いずれも、相互扶助の伝統等の地域文化あるいはその精神が残っているという共通点を持つ地域である。本稿では、前稿に引き続き、日常生活の不安と生きがい感､食生活､保健医療･福祉サービス、暮らし向きと地域の問題等についての分析結果とそのまとめを示す。将来の生活不安は島喚集落部の方が島嶼都市部よりも不安を感じる人が多かった。一方、生きがい感は、島嶼都市部の方が高かった。食生活では、栄養面のバランスを欠きやすい環境下にあった。保健医療では、島嶼集落部は医療サービスの地域格差への不満や問題が見られると同時に、健康に対するセルフケア意識の高さが伺えた。福祉サービスでは、島嶼集落部では天候や交通手段によるサービスの中止や困難性などが生じていた。暮らし向きと地域の問題では地域差はなく、共通して台風､交際費､老後の生活の不安があげられ、特に瀬戸内町で地域の問題を感じている人が多かった。The purpose of the study was to investigate the life styles and the social welfare needs of the　elderly who live on the Amami Islands and the Yaeyama Islands through a questionnaire survey. The regions surveyed were the urban area of the Amami Ohshima (Amami City) and the rural area of the Kakeroma Islands (Setouchi Town) in Kagoshima prefecture, and the urban area of Ishigaki Island (Ishigaki City) and the rural area of Iriomote Island and Hatoma Island (Taketomi Town) in Okinawa Prefecture. The people who dwell on these remote islands are usually under unfavorable conditions geographically and economically and the communities there are under functional decline due to depopulation and aging. On the other hand, these islands keep the spirit of mutual helping and the traditional cultures. In this paper we report analyses of the anxiety about future life, the feeling that life is worth living, the eating habits, the evaluation of health-care services and welfare services, the family finances, and other regional issues. The anxiety about future life was higher in the rural areas of the islands than in the urban areas. On the other hand, the feeling that life is worth living was higher in the urban areas of the islands than in the rural areas. Respondents were prone to eat poor-balanced meals. In the rural areas of the islands, while they expressed their dissatisfaction with regional gaps of health-care services, they showed high awareness of self-care about their own health. In the rural areas of the islands, welfare services at home were sometimes cancelled by bad weather or transportation trouble by sea. There was no difference in the family finances and regional issues between areas. Regional issues shared by all islands were the vulnerability to typhoons, high social expenses, and the anxiety about life in the future, and especially the elderly in the Setouchi Town listed more regional issues than those in other areas.area of the Kakeroma Islands (Setouchi Town) in Kagoshima prefecture, and the urban area of Ishigaki Island (Ishigaki City) and the rural area of Iriomote Island and Hatoma Island (Taketomi Town) in Okinawa Prefecture. The people who dwell on these remote islands are usually under unfavorable conditions geographically and economically and the communities there are underfunctional decline due to depopulation and aging. On the other hand, these islands keep the spirit of mutual helping and the traditional cultures.In this paper we report analyses of the anxiety about future life, the feeling that life is worth living, the eating habits, the evaluation of health-care services and welfare services, the family finances, and other regional issues. The anxiety about future life was higher in the rural areas ofthe islands than in the urban areas. On the other hand, the feeling that life is worth living was higher in the urban areas of the islands than in the rural areas. Respondents were prone to eat poor-balanced meals. In the rural areas of the islands, while they expressed their dissatisfaction with regional gaps of health-care services, they showed high awareness of self-care about their own health. In the rural areas of the islands, welfare services at home were sometimes cancelled by bad weather or transportation trouble by sea. There was no difference in the family finances and regional issues between areas. Regional issues shared by all islands were the vulnerability to typhoons, high social expenses, and the anxiety about life in the future, and especially the elderly in the Setouchi Town listed more regional issues than those in other areas

SECONDARY IMPAIRMENT OF INTRACELLULAR CHOLESTEROL TRANSPORT IN CELLS WITH NIEMANN-PICK DISEASE TYPE C

Niemann-Pick disease type C (NPC) is an autosomal recessive lipidosis resulting from mutations of the NPC1 or NPC2 gene, clinically characterized by hepatosplenomegaly and progressive neurological symptoms including vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia. Neurodegeneration in NPC shows a number of pathological features similar to those observed in Alzheimer disease. Biochemically, this disease is featured by a defect in intracellular trafficking of exogenous cholesterol that leads to the lysosomal and late-endosomal accumulation of unesterified cholesterol. Some reports have shown disturbance of cholesterol efflux in cells with NPC1, or NPC2 gene mutations, resulting in plasma lipid abnormalities including low levels of high-density lipoprotein (HDL) cholesterol as part of the phenotype in NPC. To elucidate the molecular basis for low HDL cholesterol in human plasma, mRNA expressions of 4 ATP-binding cassette (ABC) transporters related to lipid metabolism, ABCA1, ABCA3, ABCA7, and ABCG1, were analyzed in fibroblasts with NPC1 gene mutations by real-time RT-PCR using hybridization probes. These analyses were performed using two fibroblasts of NPC from a patient with two novel compound heterozygous NPC1 mutations, c.1891A>G and c.581_592delinsG, and a patient with other two novel compound heterozygous NPC1 mutations, c.2800C>T and c.3418G>A. Based on these analyses, the mRNA levels of ABCA1 and ABCG1 were significantly decreased in the fibroblasts. These findings suggest that secondary dysfunctions of ABCA1 and ABCG1 may cause impairment of cholesterol efflux in the peripheral cells, leading to low plasma levels of HDL cholesterol in NPC. Second, to clarify whether the secondary acid sphingomyelinase deficiency in NPC cells is related to the intracellular pathology of NPC, we investigated the effects of an acid sphingomyelinase inducer, butyrate, on the accumulation of unesterified cholesterol in NPC cells. The results demonstrated that correction of the secondary acid sphingomyelinase deficiency could ameliorate the extent of cholesterol accumulation

No Involvement of Acid Sphingomyelinase in the Secretion of IL-6 from Alveolar Macrophages in Rat

Chronic lung disease (CLD) of the newborn is a major problem in neonatology. Activation of alveolar macrophages has been implicated in the pathogenesis of CLD. Acid sphingomyelinase (ASM) responds to diverse cellular stressors, including lipopolysaccharide (LPS) stimulation. Recently, functional inhibitors of acid sphingomyelinase (FIASMAs) have been described as a large group of compounds that inhibit ASM. Here, we used maternal intra-peritoneal LPS injection to model CLD in the infant rat lung. Using this model, we studied ASM activity in the infant rat lung and the effects of FIASMAs on release of interleukin-6 (IL-6) from LPS-stimulated alveolar macrophages. Maternal exposure to LPS non-significantly increased ASM activities in the infant rat lung. FIASMAs significantly decreased ASM activity of LPS-stimulated alveolar macrophages. In addition, some FIASMAs suppressed the release of IL-6 from LPS-stimulated alveolar macrophages during the early response phase. However, FIASMAs did not suppress the release of IL-6 from LPS-stimulated alveolar macrophages. From our study, we could not confirm that ASM activation is responsible for LPS-related pathogenesis of CLD and release of IL-6 from LPS-stimulated alveolar macrophages

BUTYRATE REDUCES FREE CHOLESTEROL ACCUMULATION IN NIEMANN-PICK DISEASE TYPE C1 CELLS (NOVA SCOTIA FORM) THROUGH THE INDUCTION OF ACID SPHINGOMYELINASE

Niemann-Pick disease type C (NPC) is an inherited disorder caused by mutations in either the NPC1 or the NPC2 gene that affect intracellular free cholesterol trafficking. Most cases of NPC have mutations in the NPC1 gene. Acid sphingomyelinase (ASM) is a lysosomal enzyme in which an inherited deficiency leads to Niemann-Pick disease types A and B (NPDA/NPDB). Despite having a normal ASM gene, NPC cells have a secondary defect in ASM activity ; the mechanism remains to be fully elucidated. Butyrate, one of the short chain fatty acids, is known as an inducer of ASM. We investigated the effects of butyrate on ASM activity and mRNA expression in normal and NPC1 mutant (Nova Scotia form ; NPC1^) lymphoblasts. After incubation with 10 mM butyric acid for 24 h, ASM activity was significantly increased by 3.3- and 4.6-fold in normal and NPC1^ cells, respectively (p cells was restored to normal levels by treatment of 10 mM butyric acid. In quantitative RT-PCR analysis, butyric acid significantly increased ASM mRNA levels in both types of cells (p lymphoblasts. Free cholesterol levels in cells treated with or without 10 mM butyric acid were 0.019±0.002 and 0.026±0.006 μg/μg protein, respectively, demonstrating that butyric acid significantly decreased free cholesterol levels in NPC1^ cells (p cells, NPDB and NPC1^ fibroblasts were treated with 10 mM butyric acid and stained with filipin. We found that butyric acid dramatically reduced the accumulation of intracellular free cholesterol in NPC1^ cells, but it did not affect NPDB cells. These data suggest that ASM induced by butyrate is related to intracellular cholesterol trafficking and metabolism in NPC1^ cells. ASM inducers, such as butyrate, may reduce the accumulation of intracellular free cholesterol in NPC1^ cells