Transcriptional activation of the Lats1 tumor suppressor gene in tumors of CUX1 transgenic mice

<p>Abstract</p> <p>Background</p> <p><it>Lats1 </it>(large tumor suppressor 1) codes for a serine/threonine kinase that plays a role in the progression through mitosis. Genetic studies demonstrated that the loss of LATS1 in mouse, and of its ortholog <it>wts </it>(warts) in Drosophila, is associated with increased cancer incidence. There are conflicting reports, however, as to whether overexpression of <it>Lats1 </it>inhibits cell proliferation. CUX1 is a transcription factor that exists in different isoforms as a result of proteolytic processing or alternative transcription initiation. Expression of p110 and p75 CUX1 in transgenic mice increases the susceptibility to cancer in various organs and tissues. In tissue culture, p110 CUX1 was shown to accelerate entry into S phase and stimulate cell proliferation.</p> <p>Results</p> <p>Genome-wide location arrays in cell lines of various cell types revealed that <it>Lats1 </it>was a transcriptional target of CUX1. Scanning ChIP analysis confirmed that CUX1 binds to the immediate promoter of <it>Lats1</it>. Expression of <it>Lats1 </it>was reduced in cux1^-/-MEFs, whereas it was increased in cells stably or transiently expressing p110 or p75 CUX1. Reporter assays confirmed that the immediate promoter of <it>Lats1 </it>was sufficient to confer transcriptional activation by CUX1. <it>Lats1 </it>was found to be overexpressed in tumors from the mammary gland, uterus and spleen that arise in p110 or p75 CUX1 transgenic mice. In tissue culture, such elevated LATS1 expression did not hinder cell cycle progression in cells overexpressing p110 CUX1.</p> <p>Conclusion</p> <p>While inactivation of <it>Lats1</it>/<it>wts </it>in mouse and Drosophila can increase cancer incidence, results from the present study demonstrate that <it>Lats1 </it>is a transcriptional target of CUX1 that can be overexpressed in tumors of various tissue-types. Interestingly, two other studies documented the overexpression of <it>LATS1 </it>in human cervical cancers and basal-like breast cancers. We conclude that, similarly to other genes involved in mitotic checkpoint, cancer can be associated with either loss-of-function or overexpression of <it>Lats1</it>.</p

Severe accidental colchicine poisoning by the autumn crocus: A case of successful treatment

AbstractBackgroundThe common garden plant autumn crocus contains colchicine and its derivatives. Colchicine poisoning causes abdominal cramps and diarrhea within hours. Several days later, multiorgan failure, pancytopenia, and cardiovascular collapse occur.1,2 Severe colchicine poisoning is associated with high mortality.Case reportA 63-year-old woman who accidentally ingested an autumn crocus, which contained ∼0.38 mg colchicine, had severe vomiting and was taken to an emergency center. She presented with symptoms of gastroenterocolitis within 1 hour of ingestion, and bone marrow hypoplasia with pancytopenia developed on the 3rd day after ingestion. We continued administration of granulocyte colony-stimulating factor (300 μg) for 5 days until we confirmed that the patient's white blood cell count was increasing. Also, there was focal and segmental intestinal ischemia and some cakes of charcoal remained in the intestinal tract. Therefore, we presumed that nonocclusive mesenteric ischemia was caused by hypotension with severe dehydration, although pseudo-obstruction due to the activated charcoal may have been a contributing factor. We were able to promptly intervene to treat paralytic ileus and gastrointestinal edema before anticipated worsening of abdominal compartment syndrome, by conducting open peritoneal drainage. Despite severe poisoning, our patient survived with intensive care. Conclusion: Colchicine intoxication may lead to a sudden and extreme critical course. Therefore, as there is no means to predict prognosis from initial severity of symptoms at onset, we suggest that all patients suspected of colchicine intoxication should be managed in hospital with continuous vital sign monitoring and frequent laboratory testing for at least a few days after ingestion

Molecular Dissection of the α-Dystroglycan- and Integrin-binding Sites within the Globular Domain of Human Laminin-10

This research was originally published in the Journal of Biological Chemistry. Hiroyuki Ido, Kenji Harada, Sugiko Futaki, Yoshitaka Hayashi, Ryoko Nishiuchi, Yuko Natsuka, Shaoliang Li, Yoshinao Wada, Ariana C. Combs, James M. Ervasti and Kiyotoshi Sekiguchi. Molecular Dissection of the α-Dystroglycan- and Integrin-binding Sites within the Globular Domain of Human Laminin-10. J. Biol. Chem. 2004; 279: 10946-10954 © the American Society for Biochemistry and Molecular Biolog

Long-chain monounsaturated fatty acids improve endothelial function with altering microbial flora

Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE−/− mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes and/ or Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease

CUX1 transcription factor is required for optimal ATM/ATR-mediated responses to DNA damage

The p110 Cut homeobox 1 (CUX1) transcription factor regulates genes involved in DNA replication and chromosome segregation. Using a genome-wide-approach, we now demonstrate that CUX1 also modulates the constitutive expression of DNA damage response genes, including ones encoding ATM and ATR, as well as proteins involved in DNA damage-induced activation of, and signaling through, these kinases. Consistently, RNAi knockdown or genetic inactivation of CUX1 reduced ATM/ATR expression and negatively impacted hallmark protective responses mediated by ATM and ATR following exposure to ionizing radiation (IR) and UV, respectively. Specifically, abrogation of CUX1 strongly reduced ATM autophosphorylation after IR, in turn causing substantial decreases in (i) levels of phospho-Chk2 and p53, (ii) γ-H2AX and Rad51 DNA damage foci and (iii) the efficiency of DNA strand break repair. Similarly remarkable reductions in ATR-dependent responses, including phosphorylation of Chk1 and H2AX, were observed post-UV. Finally, multiple cell cycle checkpoints and clonogenic survival were compromised in CUX1 knockdown cells. Our results indicate that CUX1 regulates a transcriptional program that is necessary to mount an efficient response to mutagenic insult. Thus, CUX1 ensures not only the proper duplication and segregation of the genetic material, but also the preservation of its integrity

オカラ豆乳の乳酸発酵処理がラットの脂質代謝に及ぼす影響

This study examined the effects of fermented soymilk and okara on lipid metabolism in rats. Fermented soymilk and okara was prepared from a mixture of soymilk and okara blended in a ratio of 2 to 1 on dry basis by lactic acid fermentation using Lactobacillus delbrueckii. Male Sprague-Dawley rats were fed a diet based on the AIN-93 diet（ control diet） or two kinds of test diets in which 20% of a control diet was replaced by unfermented soymilk/okara mixture or fermented soymilk/okara for 7 weeks. We investigated changes in plasma and hepatic lipid levels of rats, and the regulation of gene expression in mesenteric adipose tissue and liver by DNA microarray. Groups of test diet significantly reduced plasma cholesterol levels compared with the control diet. In addition, the hepatic triglyceride in rats fed test diets was significantly lower than that of control diet. DNA microarray analysis indicated that the test diet ingestion down-regulated the expression of genes related to lipid metabolism in mesenteric adipose tissue and liver. These results suggested that a mixture of soymilk and okara has the effect improving lipid metabolism. Especially, fermented soymilk and okara seems to promote the restraint of abdominal visceral fat accumulation in comparison with unfermented soymilk and okara. Therefore, fermented soymilk and okara is a functional food showing effect preventing metabolic syndrome

ラット脂質代謝に影響を及ぼす豆乳の有効濃度について

It is known that soy protein has the hypolipidemic action on blood and liver. We investigated to clarify physiologically effective concentration of soymilk. Male Sprague-Dawley rats aged 7weeks were fed a control die（t AIN-93G, soy protein free）, or a test diet in which 10.78%（corresponding to soy protein 5%）or 21.55%（corresponding to soy protein 10%）of the diet was replaced with soymilk, respectively. The rats were fed the control diet or the test diet for 5weeks. The administration of soymilk significantly suppressed total cholesterol level in plasma and decreased liver lipid and visceral fat. These effects depended on the concentration of administrated soymilk. It was suggested that soymilk improved the lipid metabolism in rat. Moreover, it was found that the administration of amount of soymilk corresponding to more than 10% soy protein was necessary to obtain a significant physiological effect in a short period

A study on health control for cadets in sea training 1. : body composition and blood circulation among cadets in sea training

東京水産大学海洋システム工学講座東京水産大学水産資源経営講座東京水産大学練習船海鷹丸東京水産大学練習船海鷹丸東京水産大学練習船海鷹丸東京水産大学練習船海鷹丸東京水産大学練習船海鷹丸東京水産大学練習船青鷹丸東京水産大学練習船青鷹丸東京水産大学名誉教

Cognitive and Psychological Reactions of the General Population Three Months After the 2011 Tohoku Earthquake and Tsunami

BACKGROUND: The largest earthquake on record in Japan (magnitude 9.0) occurred on March 11, 2011, and the subsequent tsunami devastated the Pacific coast of Northern Japan. These further triggered the Fukushima I nuclear power plant accidents. Such a hugely complex disaster inevitably has negative psychological effects on general populations as well as on the direct victims. While previous disaster studies enrolled descriptive approaches focusing on direct victims, the structure of the psychological adjustment process of people from the general population has remained uncertain. The current study attempted to establish a path model that sufficiently reflects the early psychological adaptation process of the general population to large-scale natural disasters. METHODS AND FINDINGS: Participants from the primary disaster area (n = 1083) and other areas (n = 2372) voluntarily participated in an online questionnaire study. By constructing path models using a structural equation model procedure (SEM), we examined the structural relationship among psychological constructs known related to disasters. As post-traumatic stress symptoms (PTS) were significantly more present in people in the primarily affected area than in those in secondary- or non-affected areas, the path models were constructed for the primary victims. The parsimoniously depicted model with the best fit was achieved for the psychological-adjustment centered model with quality of life (QoL) as a final outcome. CONCLUSION: The paths to QoL via negative routes (from negative cognitive appraisal, PTS, and general stress) were dominant, suggesting the importance of clinical intervention for reducing negative cognitive appraisal, and for caring for general stress and PTS to maintain QoL at an early stage of psychological adaptation to a disaster. The model also depicted the presence of a positive route where positive cognitive appraisal facilitates post-traumatic growth (PTG) to achieve a higher QoL, suggesting the potential importance of positive psychological preventive care for unexpected natural disasters

「緩和ケアを推進する看護師教育プログラム」の評価 : 修了者およびその上司への調査から

京都府立医科大学医学部看護学科京都府立医科大学附属病院看護部京都府立医科大学看護実践キャリア開発センター京都府立医科大学附属病院地域医療推進部School of Nursing, Kyoto Prefectural University of MedicineDepartment of Nursing, University Hospital Kyoto Prefectural University of MedicineKyoto Prefectural University of Medicine, Career Development Center for NursingPromotion Division of Regional Medicine, University Hospital Kyoto Prefectural University of Medicine　本研究の目的は、「緩和ケア実践看護師養成コース（以下Aコース）」「在宅緩和ケア推進看護師養成コース（以下Bコース）」を受講した修了者とその上司への調査からプログラム評価および看護実践への活用状況を指標にしてプログラムを評価することである。【方法】平成27～31年度の間に京都府立医科大学看護実践キャリア開発センターが開催する「緩和ケアを推進する看護師教育プログラム」のAコースまたはBコースを受講した修了者25名のうち、調査時点で受講時と同じ施設・病院で就労を継続している21名（Aコース14名、Bコース7名）、とその上司21名（Aコース14名、Bコース7名）を研究対象者とした。修了生の施設・病院に質問紙を郵送し、令和3年7月～8月に無記名の自記式質問紙調査を行った。調査項目は、基本属性、カリキュラムについて、教育目標について、受講内容の適切性について、学習内容の臨床での活用について、とした。なお所属する大学の医学倫理審査委員会の承認を得て実施した（ERB-E-444）。【結果】回答者は、Aコース修了者9名、Aコース上司7名、Bコース修了者5名、Bコース上司3名であった。受講した修了者の評価においては、プログラムの内容についてAコースの8割以上が、Bコースの全員が（とても・まあまあ）適切としている。自己能力の発揮状況について、Aコースは4～6割、Bコースについては4～8割ができているとしている。　上司からの評価では、両コースとも受講した講義・演習・実習が7割程度現在の看護実践に役立っていると答えた。期待される能力については両コースとも8割以上が現在の看護活動に活きていると答えた。【結論】平成27年度から開始された「緩和ケアを推進する看護師教育プログラム」に対して、受講した修了者とその上司に，研修が有用であったかを問うたところ、受講した修了者はプログラムの内容が看護の実践で活かされていると実感していることが明らかとなった。さらに、上司は、受講した修了者が研修を踏まえた看護実践ができていると評価していることが明らかになった。修了者、上司の評価からプログラムの効果を評価することができた