61 research outputs found

    Lipoprotein Lipase as a Candidate Target for Cancer Prevention/Therapy

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    Epidemiological studies have shown that serum triglyceride (TG) levels are linked with risk of development of cancer, including colorectal and pancreatic cancers, and their precancerous lesions. Thus, it is assumed that serum TG plays an important role in carcinogenesis, and the key enzyme lipoprotein lipase (LPL), which catalyzes the hydrolysis of plasma TG, may therefore be involved. Dysregulation of LPL has been reported to contribute to many human diseases, such as atherosclerosis, chylomicronaemia, obesity, and type 2 diabetes. Recently, it has been reported that LPL gene deficiency, such as due to chromosome 8p22 loss, LPL gene polymorphism, and epigenetic changes in its promoter region gene, increases cancer risk, especially in the prostate. In animal experiments, high serum TG levels seem to promote sporadic/carcinogen-induced genesis of colorectal and pancreatic cancers. Interestingly, tumor suppressive effects of LPL inducers, such as PPAR ligands, NO-1886, and indomethacin, have been demonstrated in animal models. Moreover, recent evidence that LPL plays important roles in inflammation and obesity implies that it is an appropriate general target for chemopreventive and chemotherapeutic agents

    CLIC4, an Intracellular Chloride Channel Protein, Is a Novel Molecular Target for Cancer Therapy

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    Chloride intracellular channel (CLIC)4 is a p53- and tumor necrosis factor α (TNFα)-regulated chloride channel protein that is localized to the mitochondria and cytoplasm of mouse and human keratinocytes. CLIC4 protein increases in differentiating keratinocytes and in keratinocytes exposed to DNA-damaging agents and metabolic inhibitors. Increasing CLIC4 levels by transduction of recombinant CLIC4 causes apoptosis. CLIC4 translocates to the nucleus under a variety of conditions of cell stress, and nuclear CLIC4 is associated with cell cycle arrest and accelerated apoptosis. Reduction of CLIC4 and several other CLIC family members by expressing a doxycycline-regulated CLIC4 antisense also causes apoptosis in squamous cancer cell lines. Expressing antisense CLIC4 in tumors derived from transplanting these cells into nude mice inhibits tumor growth, increases tumor apoptosis, and reduces tumor cell proliferation. Co-administration of TNFα intraperitoneally enhances the tumor-inhibitory influence of CLIC4 antisense expression. Together, these results suggest that CLIC4 is important for keratinocyte viability and may be a novel target for anti-cancer therapy

    Theracurmin inhibits intestinal polyp development in Apc‐mutant mice by inhibiting inflammation‐related factors

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    Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Therefore, it is important to establish useful methods for preventing CRC. One prevention strategy involves the use of cancer chemopreventive agents, including functional foods. We focused on the well‐known cancer chemopreventive agent curcumin, which is derived from turmeric. However, curcumin has the disadvantage of being poorly soluble in water due to its high hydrophobicity. To overcome this problem, the formation of submicron particles with surface controlled technology has been applied to curcumin to give it remarkably improved water solubility, and this derived compound is named Theracurmin. To date, the preventive effects of Theracurmin on hereditary intestinal carcinogenesis have not been elucidated. Thus, we used Apc‐mutant mice, a model of familial adenomatous polyposis, to evaluate the effects of Theracurmin. First, we showed that treatment with 10‐20 µM Theracurmin for 24 hours reduced nuclear factor‐κB (NF‐κB) transcriptional activity in human colon cancer DLD‐1 and HCT116 cells. However, treatment with curcumin mixed in water did not change the NF‐κB promoter transcriptional activity. As NF‐κB is a regulator of inflammation‐related factors, we next investigated the downstream targets of NF‐κB: monocyte chemoattractant protein‐1 (MCP‐1) and interleukin (IL)‐6. We found that treatment with 500 ppm Theracurmin for 8 weeks inhibited intestinal polyp development and suppressed MCP‐1 and IL‐6 mRNA expression levels in the parts of the intestine with polyps. This report provides a proof of concept for the ongoing Theracurmin human trial (J‐CAP‐C study)

    Resveratrol inhibits development of colorectal adenoma via suppression of LEF1; comprehensive analysis with connectivity map

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    Although many chemopreventive studies on colorectal tumors have been reported, no effective and safe preventive agent is currently available. We searched for candidate preventive compounds against colorectal tumor comprehensively from United States Food and Drug Administration (FDA)-approved compounds by using connectivity map (CMAP) analysis coupled with in vitro screening with colorectal adenoma (CRA) patient-derived organoids (PDOs). We generated CRA-specific gene signatures based on the DNA microarray analysis of CRA and normal epithelial specimens, applied them to CMAP analysis with 1309 FDA-approved compounds, and identified 121 candidate compounds that should cancel the gene signatures. We narrowed them down to 15 compounds, and evaluated their inhibitory effects on the growth of CRA-PDOs in vitro. We finally identified resveratrol, one of the polyphenolic phytochemicals, as a compound showing the strongest inhibitory effect on the growth of CRA-PDOs compared with normal epithelial PDOs. When resveratrol was administered to ApcMin/+ mice at 15 or 30 mg/kg, the number of polyps (adenomas) was significantly reduced in both groups compared with control mice. Similarly, the number of polyps (adenomas) was significantly reduced in azoxymethane-injected rats treated with 10 or 100 mg/resveratrol compared with control rats. Microarray analysis of adenomas from resveratrol-treated rats revealed the highest change (downregulation) in expression of LEF1, a key molecule in the Wnt signaling pathway. Treatment with resveratrol significantly downregulated the Wnt-target gene (MYC) in CRA-PDOs. Our data demonstrated that resveratrol can be the most effective compound for chemoprevention of colorectal tumors, the efficacy of which is mediated through suppression of LEF1 expression in the Wnt signaling pathway

    Retrospective comparison of clinical and angiographic outcomes after primary stenting using sirolimus-eluting and bare-metal stents in nonrandomized consecutive 568 patients with first ST-segment elevated myocardial infarctions

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    SummaryBackground and purposeThe long-term safety and efficacy of primary stenting using drug-eluting stents (DES) in patients with ST-segment elevation myocardial infarction (STEMI) are not fully understood in Japan. Therefore, we retrospectively examined the midterm clinical and angiographic outcomes in STEMI patients after primary stenting using sirolimus-eluting stents (SES) in a clinical setting through a historical comparison with those of bare-metal stents (BMS).Methods and resultsThe study design was a retrospective, nonrandomized, and single-center study. The clinical outcomes for 568 consecutive patients who presented within 12h of their first STEMI and who were treated with BMS (n=198; 184 STEMIs from June 2003 to August 2004 and 14 STEMIs from September 2004 to May 2007) or SES (n=370; from August 2004 to May 2007) at our medical center in Japan were retrospectively investigated in February 2010. The incidence of post-discharge events (comprising cardiac death and nonfatal recurrent MI) after SES placement (3.9%) was not significantly different from that after BMS placement (6.7%). SES was not related to the risk of post-discharge events (mean follow-up for SES, 1327±415 days; BMS, 1818±681 days) (hazard ratio of 0.369 at 95% CI, 0.119–1.147, p=0.085). The incidence of definite stent thromboses after SES placement (0.54%) was not significantly higher than that after BMS placement (0%). The incidence of binary in-stent restenosis (% diameter stenosis of more than 50% at secondary angiography) after SES placement (8.3%) was significantly lower than that after BMS placement (25.7%; p<0.001).ConclusionsFrom the present historical comparison of SES and BMS, we conclude that primary stenting using SES in a clinical setting has favorable clinical and angiographic outcomes in Japanese STEMI patients

    Intensive endoscopic resection for downstaging of polyp burden in patients with familial adenomatous polyposis (J-FAPP Study III) : a multicenter prospective interventional study

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    Background Total colectomy is the standard treatment for familial adenomatous polyposis (FAP). Recently, an increasing number of young patients with FAP have requested the postponement of surgery or have refused to undergo surgery. We aimed to evaluate the effectiveness of intensive endoscopic removal for downstaging of polyp burden (IDP) in FAP. Method A single-arm intervention study was conducted at 22 facilities. Participants were patients with FAP, aged ≥ 16 years, who had not undergone colectomy or who had undergone colectomy but had ≥ 10 cm of large intestine remaining. For IDP, colorectal polyps of ≥ 10 mm were removed, followed by polyps of ≥ 5 mm. The primary end point was the presence/absence of colectomy during a 5-year intervention period. Results 222 patients were eligible, of whom 166 had not undergone colectomy, 46 had undergone subtotal colectomy with ileorectal anastomosis, and 10 had undergone partial resection of the large intestine. During the intervention period, five patients (2.3 %, 95 % confidence interval [CI] 0.74 %–5.18 %) underwent colectomy, and three patients died. Completion of the 5-year intervention period without colectomy was confirmed in 150 /166 patients who had not undergone colectomy (90.4 %, 95 %CI 84.8 %–94.4 %) and in 47 /56 patients who had previously undergone colectomy (83.9 %, 95 %CI 71.7 %–92.4 %). Conclusion IDP in patients with mild-to-moderate FAP could have the potential to be a useful means of preventing colorectal cancer without implementing colectomy. However, if the IDP protocol was proposed during a much longer term, it may not preclude the possibility that a large proportion of colectomies may still need to be performed

    Literature Review on Intervention Studies to Enhance Resilience of Nurses

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    本研究では、国内外で報告されている看護師のレジリエンスを高める介入研究をレビューし、実施方法および有効性について示唆を得ることを目的に文献検討を行った。国内文献は、医学中央雑誌web 版とGoogle Scholar を用いて「レジリエンス」AND「看護師」をキーワードに原著論文に限定した。国外文献は、Pub Med、Scopus を用いて、「resilience」AND「nurse」をキーワードに2013 ~ 2023 年の10 年間とした。国内文献1302 件、国外文献513 件から、関連要因を検討した文献、患者や学生を対象とした文献、尺度開発、概念分析、実態調査、重複論文は除外し、19 件の文献を分析対象とした。看護師のレジリエンスを高めるプログラムの構成では、対面の他、在宅トレーニングやオンラインを用いた介入も行われていた。プログラムの内容は、認知行動療法や心理学教育に基づき、多種多様な介入がみられ、複数のプログラムを組み合わせて行っていた。介入の有効性を評価する指標は、レジリエンスの他、ストレス、不安、抑うつ、自己効力感、燃え尽き症候群、セルフコンパッション、生活の質に関する尺度等が用いられていた。文献検討を行ったほとんどの研究が肯定的であり、有益な介入であると結論付けていた。 以上から、看護師のレジリエンスを高める介入は、レジリエンスのどの概念を強化するのかの目標を定め、これに基づき対象者に応じた実現可能なプログラムを構築し、目標を評価する適切な指標を用いて検証することが要点となると考えられた。そして、看護師のレジリエンスを高めるための介入研究を積み重ね検証していく必要性が示唆された。departmental bulletin pape
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