NPRL-Z-1, as a New Topoisomerase II Poison, Induces Cell Apoptosis and ROS Generation in Human Renal Carcinoma Cells

NPRL-Z-1 is a 4β-[(4″-benzamido)-amino]-4′-O-demethyl-epipodophyllotoxin derivative. Previous reports have shown that NPRL-Z-1 possesses anticancer activity. Here NPRL-Z-1 displayed cytotoxic effects against four human cancer cell lines (HCT 116, A549, ACHN, and A498) and exhibited potent activity in A498 human renal carcinoma cells, with an IC50 value of 2.38 µM via the MTT assay. We also found that NPRL-Z-1 induced cell cycle arrest in G1-phase and detected DNA double-strand breaks in A498 cells. NPRL-Z-1 induced ataxia telangiectasia-mutated (ATM) protein kinase phosphorylation at serine 1981, leading to the activation of DNA damage signaling pathways, including Chk2, histone H2AX, and p53/p21. By ICE assay, the data suggested that NPRL-Z-1 acted on and stabilized the topoisomerase II (TOP2)–DNA complex, leading to TOP2cc formation. NPRL-Z-1-induced DNA damage signaling and apoptotic death was also reversed by TOP2α or TOP2β knockdown. In addition, NPRL-Z-1 inhibited the Akt signaling pathway and induced reactive oxygen species (ROS) generation. These results demonstrated that NPRL-Z-1 appeared to be a novel TOP2 poison and ROS generator. Thus, NPRL-Z-1 may present a significant potential anticancer candidate against renal carcinoma

Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20( S )-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents

Twelve novel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate

[[alternative]]A Study on the Decision Making Structure for Selecting Mathematics Textbook by Elementary School Teachers and Their Posterior Usage Satisfaction

[[abstract]]　　本研究旨在探討雲林縣國小教師對數學教科書選用考量因素與使用滿意度之情形，及意見被處理強度與下一次選用的關係，研究目的做為教科書出版業者編輯與國小教師選用之參考依據。　　　　本研究之母群體為雲林縣國小低年級教師，依學校規模分層抽取100所學校，針對418位目前任教低年級之教師進行施測，問卷回收後，共計有效樣本407份。 　　　　本研究採用問卷調查法，並以自編之「國小教師對數學教科書選用考量因素與使用滿意度問卷」作為資料蒐集的工具，根據受試教師問卷填答結果，以描述性統計、t考驗、單因子變異數分析、驗證性因素分析、皮爾森相關係數等統計方法，進行資料處理分析。　　　　主要研究結果如下： 一. 國小教師在選用數學教科書時，高度認同物理屬性、出版商屬性、教材內容屬性、教學設計屬性等考量因素。二. 國小教師對於目前所使用的數學教科書滿意度頗高。三. 參與教科書選用的教師，在教科書的物理屬性、出版商屬性滿意度大於不參與教科書選用的教師，但差異性不大。四. 擔任低年級教學年資2年到4年的教師，對教科書之教材內容屬性的滿意度顯著大於其他教學年資的教師。五. 當數學教科書是必要補充教材時，在教科書的教材內容、教學設計屬性的滿意度，是教師的重要參考因素。六. 影響教師滿意度最主要的因素在於選用因素中的「教學設計屬性」與「物理屬性」兩個層面。[[abstract]]　　The purpose of this research is aimed at investigating the relationship and consideration factors for the selection of a mathematics textbook and the subsequent usage satisfaction of elementary school teachers, as well as the differences in the background of elementary school teachers, and Yunlin County as a sample source.　　　　The participants in this study were lower grade elementary school teachers in Yunlin Country. 418 lower grade teachers from 100 elementary schools were used as a stratified sampling. Actual reclaim of valid samples were 407.　　　　This research adopted questionnaire method is self-editing based “Survey of the consideration factors for the selection of a mathematics textbook and the subsequent usage satisfaction of elementary school teachers” to collect information. All quantitative data has been analyzed via some statistical methods including descriptive statistics, T-test, one-way ANOVA, confirmatory factor analysis and Pearson product-moment correlation.　　　　The major results were summarized as follows:1. The consideration factors for the selection of a mathematics textbook were generally identified by lower grade teachers, which include physical-related attributes, publication-related attributes, context-related attributes and instructional design attributes of textbook.2. The lower grade teachers were highly satisfied with the mathematics textbooks used at present. 3. With the slight difference, the teachers participating in the textbook selection showed high satisfaction in physical-related attributes and publication-related attributes of the textbook.4. In comparing with the experience of lower grade teaching, the teachers from the group of 2 to 4 years had higher satisfaction about the textbook context-related attributes than the others.5. The teachers will emphasize the high satisfaction of the textbook context-related attributes and instructional design attributes, when the textbooks were used to be the complementary materials.6. The main factors affecting teacher satisfaction degree in the selection factors lie in “instructional design attributes” and “physical-related attributes”

Assurance of Medical Device Quality with Quality Management System: An Analysis of Good Manufacturing Practice Implementation in Taiwan

The implementation of an effective quality management system has always been considered a principal method for a manufacturer to maintain and improve its product and service quality. Globally many regulatory authorities incorporate quality management system as one of the mandatory requirements for the regulatory control of high-risk medical devices. The present study aims to analyze the GMP enforcement experience in Taiwan between 1998 and 2013. It describes the regulatory implementation of medical device GMP requirement and initiatives taken to assist small and medium-sized enterprises in compliance with the regulatory requirement. Based on statistical data collected by the competent authority and industry research institutes, the present paper reports the growth of Taiwan local medical device industry after the enforcement of GMP regulation. Transition in the production, technologies, and number of employees of Taiwan medical device industry between 1998 and 2013 provides the competent authorities around the world with an empirical foundation for further policy development

Survey of knowledge, self-efficacy, and attitudes toward suicide prevention among nursing staff

Abstract Objective This study aimed to explore the knowledge, self-efficacy, and attitudes toward suicide prevention among nurses with different demographic characteristics. Methods A cross-sectional descriptive design was adopted, and the study was conducted between August and September 2020. The content of the questionnaire included basic demographics, knowledge, self-efficacy, and attitudes toward suicide prevention. Correlation analysis was performed to determine nurses’ knowledge, self-efficacy, and attitudes toward suicide prevention. Results The sample comprised 778 nursing staff from a medical center in southern Taiwan. The results showed that age, years of nursing experience, department type, education on suicide prevention, and care experience of nursing staff were associated with their knowledge, self-efficacy, and attitudes toward suicide prevention in general hospital patients. Younger and less experienced nurses demonstrated superior knowledge, self-efficacy, and attitudes toward suicide prevention. Nurses who received suicide-related education and training exhibited better self-efficacy and attitudes than those who did not. Nurses with care experience had better knowledge of suicide prevention than those without experience. Knowledge and self-efficacy in suicide prevention were both significantly and positively correlated with attitudes. Conclusion Younger, less experienced, psychiatric nurses demonstrated superior knowledge, self-efficacy, and attitudes toward suicide prevention. Therefore, education on suicide prevention should be strengthened for older, experienced, and non-psychiatric nurses

α-Tomatine affected mitochondrial apoptotic or anti-apoptotic protein levels.

<p>(<b>A</b>) α-Tomatine induced Mcl-1s and Bak up-regulations (pro-apoptotic) but did not affect Bcl-2 and Bid protein levels in the HL60 cells. (<b>B</b>) In the K562 cells, α-tomatine significantly enhanced the activation of Bak and up-regulated Mcl-1s; however α-tomatine did not influence Bcl-2 and Bid protein expressions. Both cell lines were treated with 5 µM α-tomatine for the indicated intervals. Data are expressed from at least three separate determinations.</p

α-Tomatine-Mediated Anti-Cancer Activity <em>In Vitro</em> and <em>In Vivo</em> through Cell Cycle- and Caspase-Independent Pathways

<div><p>α-Tomatine, a tomato glycoalkaloid, has been reported to possess antibiotic properties against human pathogens. However, the mechanism of its action against leukemia remains unclear. In this study, the therapeutic potential of α-tomatine against leukemic cells was evaluated <em>in vitro</em> and <em>in vivo</em>. Cell viability experiments showed that α-tomatine had significant cytotoxic effects on the human leukemia cancer cell lines HL60 and K562, and the cells were found to be in the Annexin V-positive/propidium iodide-negative phase of cell death. In addition, α-tomatine induced both HL60 and K562 cell apoptosis in a cell cycle- and caspase-independent manner. α-Tomatine exposure led to a loss of the mitochrondrial membrane potential, and this finding was consistent with that observed on activation of the Bak and Mcl-1 short form (Mcl-1s) proteins. Exposure to α-tomatine also triggered the release of the apoptosis-inducing factor (AIF) from the mitochondria into the nucleus and down-regulated survivin expression. Furthermore, α-tomatine significantly inhibited HL60 xenograft tumor growth without causing loss of body weight in severe combined immunodeficiency (SCID) mice. Immunohistochemical test showed that the reduced tumor growth in the α-tomatine-treated mice was a result of increased apoptosis, which was associated with increased translocation of AIF in the nucleus and decreased survivin expression <em>ex vivo</em>. These results suggest that α-tomatine may be a candidate for leukemia treatment.</p> </div

Effects of α-tomatine on the mitochondrial membrane potential in both HL60 and K562 cell lines.

<p>The mitochondrial membrane potential was quantitated by flow cytometric analysis with rhodamine 123. The (<b>A</b>) HL60 and (<b>B</b>) K562 cell lines were treated with 10 µM rhodamine 123 and incubated at 37°C for 30 min in the presence of 5 µM α-tomatine. The horizontal axis shows the relative fluorescence intensity, and the vertical axis indicates the cell number. The green curve indicates the control. The blue curve indicates the α-tomatine-treated cells. A shift from the green curve to the blue curve indicates a loss of mitochondrial membrane potential. Data are expressed from at least three separate determinations.</p