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PDF file, 61K, Effect of MCT1 knockdown on ROS accumulation.

PDF file, 52K, Effect of MCT1 knockdown on mitochondrial mass.

PDF file, 336K, Differential effects of siMCT1 vs siMCT2 on the growth of colon cancer cells.

Senescence, an inherent tumor suppressive mechanism, is a critical determinant for chemotherapy. In the present study, we show that the monocarboxylate transporter 2 (MCT2) protein was tumor-selectively expressed in human colorectal malignancies and knockdown of MCT2 induces mitochondrial dysfunction, cell-cycle arrest, and senescence without additional cellular stress in colorectal cancer cell lines. Moreover, the reactive oxygen species (ROS) scavenger, N-acetylcysteine, blocked MCT2 knockdown-induced growth arrest and cellular senescence, indicating a pivotal role of ROS in this pathway. Dramatic induction of mitochondrial superoxide generation and decrease in ATP production was observed, indicating that mitochondrial dysfunction is the major mechanism underlying MCT2 knockdown-induced ROS generation. Senescence-associated DNA damage was also evident from the increase in promyelocytic leukemia bodies, γH2AX foci, and SAHF. Conversely, overexpression of MCT2 prevented doxorubicin-induced ROS accumulation (P = 0.0002) and cell growth inhibition (P = 0.001). MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo. In addition, MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect. These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer. Mol Cancer Ther; 11(11); 2342–51. ©2012 AACR.

Supplementary Figure 1 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Supplementary Figure 5 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Supplementary Figure 6 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Ras associated with diabetes (Rad) is a Ras-related GTPase that promotes cell growth by accelerating cell cycle transitions. Rad knockdown induced cell cycle arrest and premature senescence without additional cellular stress in multiple cancer cell lines, indicating that Rad expression might be critical for the cell cycle in these cells. To investigate the precise function of Rad in this process, we used human Rad as bait in a yeast two-hybrid screening system and sought Rad-interacting proteins. We identified the Grap2 and cyclin D interacting protein (GCIP)/DIP1/CCNDBP1/HHM, a cell cycle–inhibitory molecule, as a binding partner of Rad. Further analyses revealed that Rad binds directly to GCIP in vitro and coimmunoprecipitates with GCIP from cell lysates. Rad translocates GCIP from the nucleus to the cytoplasm, thereby inhibiting the tumor suppressor activity of GCIP, which occurs in the nucleus. Furthermore, in the presence of Rad, GCIP loses its ability to reduce retinoblastoma phosphorylation and inhibit cyclin D1 activity. The function of Rad in transformation is also evidenced by increased telomerase activity and colony formation according to Rad expression level. In vivo tumorigenesis analyses revealed that tumors derived from Rad knockdown cells were significantly smaller than those from control cells (P = 0.0131) and the preestablished tumors are reduced in size after the injection of siRad (P = 0.0064). Therefore, we propose for the first time that Rad may promote carcinogenesis at least in part by inhibiting GCIP-mediated tumor suppression. Cancer Res; 70(11); 4357–65. ©2010 AACR.

Supplementary Table 1 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Supplementary Table 2 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Supplementary Figure 2 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Supplementary Figure 4 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Supplementary Figure Legends 1-6 from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment

Glioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM. In this study, high-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on GBM cell lines, LN229, U87 and T98G. Cough suppressants, oxelaidin and butamirate inhibited GBM growth. A Ras family GTPase, Ras-related associated with diabetes (RRAD), contributes to activation of STAT3, which is essential for survival and growth of many cancer types. Interestingly, oxelaidin and butamirate did not affect proliferation in RRAD negative GBM cells. Docking simulation analyses revealed selective interactions between oxelaidin and RRAD. The mechanism by which butamirate and oxelaidin inhibits GBM cell growth involves the suppression of STAT3 transcriptional activity, leading to down-regulation of cyclin D1 and survivin. In addition, components of RRAD-associated signaling cascades, including p-EGFR, p-Akt, and p-STAT3, were inhibited upon oxelaidin treatment. Intraperitoneal administration of oxelaidin or butamirate markedly suppressed tumor growth in a glioblastoma xenograft mouse model without significant adverse effects. Our collective findings indicate that oxelaidin and butamirate exert anti-tumor effects in glioblastoma, supporting its utility as a novel therapeutic candidate for glioblastoma.

This study was conducted to develop and test a prediction model that explains health-related quality of life (HRQoL) of patients with Parkinson's disease (PD). Participants were 248 patients with PD enrolled in the neurology clinic of a university hospital in Seoul, Korea. The data were collected through structured questionnaires from March 1 to July 5, 2013. Motor fluctuations, depression, sleep disturbances, fatigue, and activities of daily living had significant direct effects on the quality of life of PD patients. Disease severity, social support, pain, sleep disturbances, fatigue, and activities of daily living had significant indirect effects on patients' quality of life. These predictive variables explained 77.4% of the total variance. The assessment of HRQoL in PD should be considered along with the variables affecting it, including social support. In addition, strategies to enhance social support may be useful for improving the quality of life for patients with PD.

Purpose: This randomized control trial was designed to examine the effect on the self-managing ability for promoting bone health of mobile type-bone health intervention (mobile type-BHI). Methods: The mobile type-BHI consisted of a mobile application called "Strong bone, Fit body" (SbFb) and group education. A total of 82 college women with low bone mass (Z score < -1) participated. They were assigned randomly to three groups, experimental group I, (n = 28), experimental group II (n = 32), and control group (n = 22). This study ran from June 2014 to January 2015. The outcome variables were bone mineral density, minerals related to bone metabolism (calcium, phosphorus, vitamin D), biochemical markers related to bone remodeling (osteocalcin, C-terminal telopeptide, sclerostin), food intake diary by 24 hours recall, and psychosocial variables related to bone health (knowledge, health belief and self-efficacy). Data were analyzed using SAS program and a computer aided nutritional analysis program. Results: Both the experimental group I, who used mobile type-BHI, and experimental group II, who only received group education, showed outcomes regarding knowledge of the benefits of exercise and calcium as compared with the control group. The two experimental groups also demonstrated results in the serum levels of calcium, vitamin D, and sclerostin compared to those of the control group. Conclusion: Although both experimental groups exhibited positive outcomes in regards to the promotion of bone health, this study did not show an additional effect of the mobile application on self-management ability for the promotion of bone health. Nonetheless, the SbFb application is very meaningful as it is the first application developed with the aim of improving women's bone health. (C) 2017 Korean Society of Nursing Science, Published by Elsevier Korea LLC.

The constitutive activation of NF-κB is a major event leading to the initiation, development, and progression of cancer. Recently, we showed that the size of preestablished tumors was reduced after the depletion of Kir2.2, an inwardly rectifying potassium channel. To determine the precise mechanism of action of Kir2.2 in the control of tumor growth, we searched for interacting proteins. Notably, NF-κB p65/RelA was identified as a binding partner of Kir2.2 in a yeast two-hybrid analysis. Further analyses revealed that Kir2.2 directly interacted with RelA in vitro and coimmunoprecipitated with RelA from cell lysates. Kir2.2 increased RelA phosphorylation at S536 and facilitated its translocation from the cytoplasm to the nucleus, thereby activating the transcription factor and increasing the expression level of NF-κB targets, including cyclin D1, matrix metalloproteinase (MMP)9, and VEGF. Kir2.2 was overexpressed in human cancer and the expression level was correlated with increased colony formation and tumor growth in mouse tumor models. On the basis of these findings, we propose an unconventional role for Kir2.2 as a constitutive RelA-activating protein, which is likely to contribute to tumor progression in vivo. Cancer Res; 73(3); 1056–62. ©2012 AACR.

Purpose: The purpose of this study was to identify social support networks for each life-cycle stage of adults. Method: A total of 1,047 subjects included 454 young adults, 262 middle-aged adults and 331 senior adults. Data were collected using Oh`s Korean Version Norbeck`s Social Support Questionnaire (NSSQ), and analyzed using descriptive statistics, t-test, and ANOVA. Result: For the young adults, parents were the top and second priority as important social support resources, the third was siblings, and then friends. For the middle-aged, spouse was the first priority as an important social support resource, while the second and the third were children. For the senior adults, children ranked from the top to the seventh priority. The mean number of social support resources was 13.23 for the young adult, 12.93 for the middle-aged and 5.30 for the senior adults. Social support networks of the young adults significantly differed according to gender and marital status. That of the middle-aged significantly differed according to family size. In addition, that of the senior adults was significantly different according to marital status, economic status, religion and family size. Conclusion: It is essential to consider social support networks for each life-cycle stage of adults when making a social support intervention program.

Purpose: The aim of this study was to develop and measure the effect of a movie-based-nursing intervention program designed to enhance motivation for rehabilitation and reduce depression levels in stroke patients. Methods: The study used a quasi-experimental, nonequivalent control group and a pretest-posttest design. The 60 research subjects were assigned to the experimental (n=30) or control group (n=30). The movie-based nursing intervention program was provided for the experimental group during 60-minute sessions held once per week for 10 weeks. The program consisted of patient education to strengthen motivation for rehabilitation and reduce depression, watching movies to identify role models, and group discussion to facilitate therapeutic interaction. Results: After 10 weeks of participation in the movie-based nursing intervention program, the experimental group’s rehabilitation motivation score was significantly higher, F=1161.54 (within groups df=49, between groups df=1), p

Purpose: l-ascorbic acid (LAA) modifies the in vitro growth of leukemic cells from ∼50% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). To test the hypothesis that depletion of LAA, alternating with supplementation to prevent scurvy, would provide therapeutic benefit, a single-arm pilot trial was conducted (ClinicalTrials.gov identifier: NCT00329498). Experimental results: During depletion phase, patients with refractory AML or MDS were placed on a diet deficient in LAA; during supplementation phase, patients received daily intravenous administration of LAA. An in vitro assay was performed pretherapy for LAA sensitivity of leukemic cells from individual patients. Results: Of 18 patients enrolled, eight of 16 evaluable patients demonstrated a clinical response. Responses were obtained during depletion (four patients) as well as during supplementation (five patients) but at a pharmacologic plasma level achievable only with intravenous administration. Of nine patients for whom the in vitro assay indicated their leukemic cells were sensitive to LAA, seven exhibited a clinical response; compared with none of six patients who were insensitive to LAA. Conclusions: The clinical benefit, along with a conspicuous absence of significant adverse events, suggests that further testing of LAA depletion alternating with pharmacologic dose intravenous supplementation in patients with these and other malignancies is warranted.

Purpose: This study aimed to explore the level of importance perceived by caregivers of elderly on the education of long term care nursing assistants (LTCNAs) taking care of elders with dementia or stroke. Method: Data was collected from 296 participants (112 families, 98 NAs, and 86 RNs) from October 2006 to February 2007. A structured questionnaire was used for data collection. Result: The item of `attitude while caring for the aged` was identified as most important. The family group reported that `position change` and `understanding of geriatric diseases` were the most important for education, while LTCNAs, highly identified, `bathing`, and `bed sheet change`. The RNs group regarded `position change`, and `bathing` as most important. Institutions demanding LTCNAs` activities were special facilities for elderly care and special hospitals for the aged, and the need was also high in families with an elder incapacitated by illness. Conclusion: Nurses need to take an interest in education for enhancing the quality of LTCNAs and thus advance the quality of nursing care as well as the quality of life for the aged.

Purpose: To identify factors influencing quality of life based on health-promoting behavior in patients with chronic illness. Design and Methods: This descriptive study was conducted over 8 months in 2001 on 1,748 chronic adult outpatients at a university hospital in Seoul, Korea. Study variables and instruments were health perception, perceived benefits of action, perceived barriers to action, self-esteem, self-efficacy, social support, commitment of planned action, activity-related affect, health-promoting behavior, and quality of life. Results: The data indicated a statistically significant positive correlation among healthpromoting behavior, perceived benefits of action, self-efficacy, social support, self-esteem, health perception, activity-related affect, and quality of life. A statistically significant negative correlation was found between perceived barriers to action and quality of life. Stepwise multiple regression showed that the most powerful predictor of quality of life was healthpromoting behavior. The combination of health-promoting behavior, activity-related affect, self-esteem, health perception, commitment to planned action, social support, and perceived barriers to action accounted for 57% of the variance in quality of life. Conclusions: Multiple social, psychological, and health-related factors were associated with quality of life.

Purpose: This study was done to assess the bone mineral density (BMD), biochemical bone turnover markers (BTMs), and factors associated with bone health in young Korean women. Methods: Participants were 1,298 women, ages 18-29, recruited in Korea. Measurements were BMD by calcaneus quantitative ultrasound, BTMs for Calcium, Phosphorus, Osteocalcin, and C-telopeptide cross-links (CTX), body composition by physical measurements, nutrients by food frequency questionnaire and psychosocial factors associated with bone health by self-report. Results: The mean BMD (Z-score) was -0.94. 8.7% women had lower BMD (Z-score≤ -2) and 14.3% women had higher BMD (Z-score≥ 0) than women of same age. BTMs were not significantly different between high-BMD (Z-score≥ 0) and low-BMD (Z-score

Purpose This study explored relationships of anger and anger expression to cardiovascular (CV) risk factors and gastrointestinal (GI) symptoms in Korean women based on hwa-byung (HB) symptoms. Methods A descriptive, comparative design was used. One-hundred four women who are from 20 to 65years old were recruited. Based on the HB score, 22 women indicated for HB and the rest were classified as normal. Data collection was done with several questionnaires including HB symptom scale, state-trait anger expression inventory, and GI symptom questionnaire and clinical information. Results Women with HB demonstrated significantly higher levels of trait anger and dysfunctional anger expression such as anger suppression and anger expression than normal group. Although blood pressure was higher in women with HB, the differences were not significant. Self-report of GI symptoms were significantly more in women with HB, however no significant difference was found in gastroscopy results. Conclusions Women with HB were younger and might lack of sufficient social support. This study suggests relationship of anger and anger expression to functional GI symptoms. Characteristics of women with HB should be considered in developing intervention programs for healthy coping. Future studies need more women with HB for better comparison.

A concise and efficient synthesis of tetracyclic azepino-indole derivatives 2 having a substituent at the angular position has been accomplished through an N-acyliminium ion cyclization. The coupling reaction of indol-3-yl-ethylamine 3 with 4-or 5-keto-acid 4 followed by cyclization reaction of the resulting tautomeric mixtures of keto-amide 5 and hydroxylactam 6 in refluxing formic acid provided 2.

The synthesis of pyrrolidine or piperidine ring-fused 2-phenyl-azepino[5,4,3- cd ]indole derivatives ( 2 ) has been accomplished through the N -acyliminium ion cyclization of hydroxy- or alkoxylactams ( 5 ) derived from cyclic anhydrides or chiral hydroxy acids.

Studies on the stereoselective synthesis of a pyrrolidinoisoquinoline derivative using acyliminium ion cyclization of hydroxylactams are described. Cyclization reaction of chiral hydroxylactams 2a∼c, derived from (L)-tartaric acid and phenethylamine, afforded one diastereomer 3 under a variety of acidic conditions in moderate to good yields.

Purpose: The purpose of this study was to construct and test a structural equation model for pressure ulcer prevention action by clinical nurses. The Health Belief Model and the Theory of Planned Behavior were used as the basis for the study. Methods: A structured questionnaire was completed by 251 clinical nurses to analyze the relationships between concepts of perceived benefits, perceived barriers, attitude, subjective norm, perceived control, intention to perform action and behavior. SPSS 22.0 and AMOS 22.0 programs were used to analyze the efficiency of the hypothesized model and calculate the direct and indirect effects of factors affecting pressure ulcer prevention action among clinical nurses. Results: The model fitness statistics of the hypothetical model fitted to the recommended levels. Attitude, subjective norm and perceived control on pressure ulcer prevention action explained 64.2% for intention to perform prevention action. Conclusion: The major findings of this study indicate that it is essential to recognize improvement in positive attitude for pressure ulcer prevention action and a need for systematic education programs to increase perceived control for prevention action.

Senescence, an inherent tumor suppressive mechanism, is a critical determinant for chemotherapy. In the present study, we show that the monocarboxylate transporter 2 (MCT2) protein was tumor-selectively expressed in human colorectal malignancies and knockdown of MCT2 induces mitochondrial dysfunction, cell-cycle arrest, and senescence without additional cellular stress in colorectal cancer cell lines. Moreover, the reactive oxygen species (ROS) scavenger, N-acetylcysteine, blocked MCT2 knockdown-induced growth arrest and cellular senescence, indicating a pivotal role of ROS in this pathway. Dramatic induction of mitochondrial superoxide generation and decrease in ATP production was observed, indicating that mitochondrial dysfunction is the major mechanism underlying MCT2 knockdown-induced ROS generation. Senescence-associated DNA damage was also evident from the increase in promyelocytic leukemia bodies, γH2AX foci, and SAHF. Conversely, overexpression of MCT2 prevented doxorubicin-induced ROS accumulation (P = 0.0002) and cell growth inhibition (P = 0.001). MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo. In addition, MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect. These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer. Mol Cancer Ther; 11(11); 2342–51. ©2012 AACR.

To understand the molecular mechanism(s) underlying bortezomib resistance, we sought to identify potential target genes that were differentially expressed in bortezomib-resistant leukemia cells versus parental controls. Microarray analysis revealed that the mRNA levels of Rad (Ras associated with diabetes) were higher in the bortezomib-resistant Jurkat (Jurkat-R) cells than in the parental control cells. The importance of Rad for bortezomib resistance was supported by three observations. First, Rad knockdown overcame bortezomib resistance and induced mitochondrial apoptosis via Noxa/Bcl-2 modulation. Second, Rad decreased cell death in response to bortezomib. Third, leukemia and lymphoma cell lines (K-562, Raji, IM-9 and Jurkat-R) with elevated Rad expression levels showed higher degrees of bortezomib resistance versus those (Sup-B15, JVM-2, U266 and Jurkat) with low Rad expression levels (r=0.48, P=0.0004). Thus, Rad over expression could be a molecular target to improve bortezomib sensitivity in human leukemia and lymphoma.

Ku70, a DNA repair protein, was recently identified as a critical anti-apoptotic protein that inhibits Bax translocation to mitochondria. The dissociation of Bax from Ku70 is essential for the apoptotic activity of Bax. Here, we show that maspin, a tumor suppressor protein frequently lost in cancer, regulates this process. Maspin increased cell death in a Ku70 acetylation-dependent manner. Maspin inhibited histone deacetylase 1 (HDAC1) and thus increased the acetylation of Ku70 and the dissociation of Bax from Ku70, which led to the induction of apoptosis. These results reveal maspin as a Ku70-interacting molecule and provide the basis for a new endogenous acetylation-based control mechanism that reduces Ku70-mediated sequestration of Bax from mitochondria.

The purpose of this study was to describe outcome indicators of nursing education including critical thinking, professionalism, leadership, and communication and to evaluate differences among nursing programs and academic years. A descriptive research design was employed. A total of 454 students from four year baccalaureate (BS) nursing programs and two three-year associate degree (AD) programs consented to complete self-administered questionnaires. The variables were critical thinking, professionalism, leadership and communication. Descriptive statistics, χ(2)-test, t-tests, ANOVA, and the Tukey test were utilized for the data analysis. All the mean scores of the variables were above average for the test instruments utilized. Among the BS students, those in the upper classes tended to attain higher scores, but this tendency was not identified in AD students. There were significant differences between BS students and AD students for the mean scores of leadership and communication. These findings suggested the need for further research to define properties of nursing educational outcomes, and to develop standardized instruments for research replication and verification.

Studies on the stereoselective synthesis of a pyrrolidinoisoquinoline derivative using acyliminium ion cyclization of hydroxylactams are described. Cyclization reaction of chiral hydroxylactams 2a∼c, derived from (L)-tartaric acid and phenethylamine, afforded one diastereomer 3 under a variety of acidic conditions in moderate to good yields.

The synthesis of pyrrolidine or piperidine ring-fused 2-phenyl-azepino[5,4,3- cd ]indole derivatives ( 2 ) has been accomplished through the N -acyliminium ion cyclization of hydroxy- or alkoxylactams ( 5 ) derived from cyclic anhydrides or chiral hydroxy acids.

A concise and efficient synthesis of tetracyclic azepino-indole derivatives 2 having a substituent at the angular position has been accomplished through an N-acyliminium ion cyclization. The coupling reaction of indol-3-yl-ethylamine 3 with 4-or 5-keto-acid 4 followed by cyclization reaction of the resulting tautomeric mixtures of keto-amide 5 and hydroxylactam 6 in refluxing formic acid provided 2.

The 4-anilinoquinazoline PD 153035 (1) is a potential antitumor agent which acts by inhibiting tyrosine kinase activity of epidermal growth factor receptor (EFGR) via competitive binding at the ATP site of enzyme. A series of cyclic analogues of PD 153035 bearing the 1,4-dioxane ring was prepared by reaction of 6-chloro derivative 5 with several aniline nucleophiles. These were evaluated for their ability to inhibit the EGFR kinase and the growth of primary human tumor cell cultures. All of the new 4-anilinoquinazolines exhibited less potency than PD 153035 against EGFR kinase. However, compounds 2b, 2c, 2e, 2g, and 2h showed higher inhibitory activities than PD 153035 against the growth of A431 tumor cell line. The compound 2b containing 3-chloroaniline ring was as potent as PD 153035 against EGFR kinase and showed about 5.4-fold better potency than PD153035 in the inhibition of growth of A431 cell line with good selectivity.

Styrylquinazoline derivatives were prepared by Perkin condensation and evaluated for inhibitory activity against HIV-1 integrase. Among them, compound 5c containing a free catechol ring was the most potent (IC(50)=0.8 +/- 1.9 microM)and showed 6-fold more potency than the corresponding styrylquinoline compound (IC(50) = 130.7 +/- 8.6 microM).