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Background. Occupational stress is a common issue faced by workers in every discipline. Complementary and alternative medicine (CAM) therapies, such as aromatherapy massage or massage, have antistress effects in the literature. The purpose of this randomized clinical trial with triple blinds is to evaluate the immediate effects of lavender aromatherapy massage for improving work stress, burnout, and HRV parameters of female employees in a university. Methods. A total of 53 subjects in experimental group whereas 57 subjects in control group completed interventions and measurement and led to power of 0.98. Inferential statistics, as independent t-test, paired t-test, and Chi-Square test, were performed to verify the expected relationships. Results. The present study found that subjects in experimental group reported a lower role stress and less inclined to type A personality trait after aromatherapy massage with lavender. For control group, only less inclined to type A personality trait was reported after receiving massage. For burnout, a significant lower personal burnout and work-related burnout were reported after aromatherapy massage whereas only increased client-related burnout was reported in control group. For HRV, both the experimental and control groups reported higher SDNN and RMSSD in time domain after intervention. Contradictory HRT and PSI in time domain were significantly lower after intervention. In frequency domain of HRV, both groups reported significantly higher value in VLF and HF. In addition, the experimental group reported significantly higher value in TP and LF after intervention. Conclusions. Both the lavender aromatherapy massage and massage did show immediate effect on different dimensions of work stress, burnout, and HRV. These two interventions can be applied as routine leisure activities by personal preference to reduce stresses occurring in work environment.

This study aims to compare the early development of professional value between the students in the traditional programme (BSN) and those in the accelerated BSN (ABSN) programmes.A longitudinal design was conducted.Data were collected from three schools of nursing during one academic year. A total of 117 BSN students and 101 ABSN students completed the survey of demographic information and the Nurses' Professional Values Scale-Revised questionnaires. All data were analysed by IBM SPSS-Statistics 22.Results showed that, in the beginning of the first professional nursing course, both students in the BSN and the ABSN programmes reported similar level of professional values. However, after one academic year, the changes in the professional value varied both between these two programmes and among the three different nursing schools. The increased professional value in school A represented the possibility for students to improve during their first-year professional nursing programme. As educators, we should redesign our teaching strategies according to the different conditions of students in each programme.

The purpose of this study was to explore the effectiveness of an essential oil massage on the sleep quality of the critical care nurses. A randomized controlled trial with single blind was conducted. A total of 112 critical care nurses were recruited. Participants were randomly allocated to either the experimental or control group. Only the experimental group received four sessions consisting of a lavender essential oil massage. The results of this study revealed that the overall subjective sleep quality and objective sleep parameters did not reach a significant difference between the two groups before and after the intervention, but a progressive the subjective sleep quality score reduction was observed in the experimental group. The findings of this study might provide information to critical care nurses who are under high pressure to find the optional alternative way of managing their self-sleep health by employing safe and convenient alternatives through aromatherapy.

(1) Background: Healthcare workplace violence has been a focused issue in the whole world. The rate of the occurrence is pretty high in every country. The emergency room is a high risk and high frequency place for violence to occur. Under the medical service demands from people, it is quite easy to bring about conflicts. This leads to serious physical and mental harm to nurses. When suffering from physical and mental injuries, resilience is a protective factor away from negative influence. It is rare to explore and study how the nurses’ resilience ability, workplace violence and turnover intention are related. Thus, the aim of this study is to understand resilience as a mediator effect in emergency nurses toward the workplace violence. (2) Methods: A cross-sectional survey study was used to collect information from emergency room nurses of a medical center in northern Taiwan. There were 132 samples in total. Three research instruments were included as follows: Hospital Workplace Violence Prevention Questionnaire, Connor-Davidson Resilience Scale, and Turnover Intention Scale. Statistical analysis using t-test, ANOVA, Correlation, as well as Sobel test were used in this study. (3) Results: The results revealed that the average age was 29.5 ± 5.6. Almost 58% of nurses experienced workplace violence. Twelve percent of nurse had experienced physical violence and 53.8% had experienced mental violence. There was significant relationship between shift personnel and religious believers. To the people who suffered physical violence, there was a significant relationship between emergency room working years and the total working years. There was significant difference between those who had suffered mental violence and religious believers. Female nurses suffered mental violence to a much higher extent than male nurses. There was a significant relationship between nurses’ working years, the total working years, resilience, and turnover intention. Resilience was not the mediator for workplace violence toward turnover intention in this study. (4) Conclusions: The outcome of this study suggested that on an individual level, nurses can enhance self-protection and communication skills to decrease workplace violence. For emergency environment settings, designing a good working environment, visitors’ restriction, avoiding working alone, and enhancing supervising alarm system are recommended. As for hospital administrators, fitness for work and to set up a project team is necessary. These can be references in planning prevention on workplace violence and promoting quality of workplace and patient safety in the future.

Clinical practice guidelines (CPGs), representing the current best-practice guidelines and recommendations for care, are supported by systematic review and evidence-based research. CPGs provide an effective and efficient approach to caring for patients and improving quality of care. Recently, the National Health Insurance Administration and National Institutes of Health developed CPGs for major diseases in Taiwan. This paper introduces the process that was used to develop one of these CPGs, the Taiwan Chronic Kidney Disease Clinical Guidelines, which was published in 2015. Further, we introduce the general development of published nursing guidelines in Taiwan. These CPGs are expected to initiate various renal-care guidelines and to promote the quality of renal care in the country.臨床診療指引的發展過程—以「台灣慢性腎臟病臨床診療指引」為例.臨床診療指引（clinical practice guidelines, CPGs），係透過系統性文獻回顧來綜整與實證相關之最佳疾病照護方式，以協助醫療團隊及病人做最適當的醫療決策，並提供具效能（effective）及效率（efficient）之照護模式，進而增進臨床照護品質。近年來，中央健康保險署與國家衛生研究院已分別針對國人常見之重大疾病出版相關之臨床指引，2015年發行之「台灣慢性腎臟病臨床診療指引」（Taiwan Chronic Kidney Disease Clinical Guidelines）即為一例。因此，本文藉簡介此臨床診療指引之重點，來說明臨床診療指引的發展過程。此外，亦介紹台灣現有之本土護理相關指引及其發展過程，期能拋磚引玉，催生腎臟護理相關指引，以提升國內腎臟照護之水準。.

Obstructive sleep apnea (OSA) is a potentially lethal respiratory sleep disorder. However, few studies have studied OSA women.The purpose of the current study was to explore the life experiences of women with OSA.A qualitative study using the grounded theory method was used to establish a descriptive theory.The results were expressed in terms of three stages with related categories. Stage 1: No interest days due to poor sleep, including "uncontrollable sleep", "perceived health deteriorates", and "poor female image harmed by snoring"; Stage 2: Indecision and disappointments during treatment seeking, including "doctor shopping", "being urged by others to seek medical help", and "being shocked by the severity of disease"; and Stage 3: Accepting a new lifestyle with a continuous positive pressure respirator, including "adaptation of the new sleep", "adequate sleep", and "secret worry of being an OSA woman".Based on the findings of the present study, medical knowledge and treatments related to OSA should be widely promoted with appropriate professional education and counseling services in order to enhance the awareness of patients and to facilitate their acceptance of the healing process using a continuous positive airway pressure respirator.阻塞性睡眠呼吸中止症婦女之生活經驗.阻塞性睡眠呼吸中止症（obstructive sleep apnea, OSA）是一種潛在致死性的睡眠呼吸紊亂性疾病，較少有關婦女方面生理或心理影響之研究，故引發探討。.探討OSA婦女之生活經驗。.本研究以紮根理論之方式，以立意取樣，共訪談10名OSA有居家使用持續陽壓呼吸器之婦女，以面對面深入訪談之方式進行資料收集，資料採持續分析與歸納，以建立OSA婦女生活經驗之描述性理論。.研究結果共分為三層面及其類屬歸納如下：一、睡眠差而提不起勁的日子：無法控制的睡眠、察覺健康變差、打鼾有損女性形象；二、一波三折的尋醫歷程：耗時摸索尋找、被催促就醫、驚覺其嚴重性；三、接受使用持續陽壓呼吸器的不一樣生活：適應新睡眠、睡飽的生活、女性生活的隱憂。.經OSA婦女之生活經驗研究結果發現， OSA醫療常識及治療應廣泛宣導，並設置專業醫療衛教小組提供持續陽壓呼吸器之相關教育與諮詢，以提升民眾疾病認知及呼吸器治療之適應。.

Indolicidin is a host defense tridecapeptide that inhibits the catalytic activity of HIV-1 integrase in vitro. Here we have elucidated its mechanism of integrase inhibition. Using crosslinking and mass spectrometric footprinting approaches, we found that indolicidin interferes with formation of the catalytic integrase-DNA complex by directly binding DNA. Further characterization revealed that the peptide forms covalent links with abasic sites. Indolicidin crosslinks single- or double-stranded DNAs and various positions of the viral cDNA with comparable efficiency. Using truncated and chemically modified peptides, we show that abasic site crosslinking is independent of the PWWP motif but involves the indolicidin unique lysine residue and the N- and C- terminal NH2 groups. Because indolicidin can also inhibit topoisomerase I, we believe that multiple actions at the level of DNA might be a common property of antimicrobial peptides.

Photodissociative experiments were performed on Cu+−C5H5N and Ag+−C5H5N complexes in the gas phase. The dissociative ligand-to-metal charge-transfer fragments, pyridine+, were observed for both complexes. Photodissociation spectra were recorded as a function of laser wavelength. Two continuous, structureless bands were investigated in each complex. Because of the low-energy 2D state of the Cu atom, the Cu+−pyridine dissociative process is more complicated. Several possible mechanisms for this process have been discussed. The binding energies were determined experimentally to be 65.5 and 45.2 kcal/mol for Cu+−pyridine and Ag+−pyridine, respectively. M+−C5H5N (M = Cu or Ag) complexes also were studied theoretically using the HF, MP2, and B3LYP methods. All complexes under study show C2v symmetry. The binding energies predicted from the theoretical calculations were less than the experimental values, which were derived from the onset of the charge-transfer appearance combined with the IP (ionization potentia...

The laser ablation technique has been employed to prepare Cu colloids from CuO powder in 2-propanol using wavelengths of 1064 and 532 nm. The copper colloids resulting from 1064 nm irradiation were conspicuously stable under aerobic conditions without any protective agent present. In addition to Cu particles, the formation of oxidized product, acetone, from 2-propanol was detected by gas chromatography. The discrepancy in the Cu colloidal formation between 1064 and 532 nm was analyzed on the basis of the absorptive ability of CuO powder, the results of the power dependence, and the measurements of the dose effect. The process of photoinduced coalescence that formed larger spherical particles was found to be wavelength-dependent. The stability of the Cu colloids could be the result of their near-perfect spherical shape and the effect of their larger size.

The molecular chaperone, heat shock protein 70 (Hsp70), is an emerging drug target for treating neurodegenerative tauopathies. We recently found that one promising Hsp70 inhibitor, MKT-077, reduces tau levels in cellular models. However, MKT-077 does not penetrate the blood-brain barrier (BBB), limiting its use as either a clinical candidate or probe for exploring Hsp70 as a drug target in the central nervous system (CNS). We hypothesized that replacing the cationic pyridinium moiety in MKT-077 with a neutral pyridine might improve its clogP and enhance its BBB penetrance. To test this idea, we designed and synthesized YM-08, a neutral analogue of MKT-077. Like the parent compound, YM-08 bound to Hsp70 in vitro and reduced phosphorylated tau levels in cultured brain slices. Pharmacokinetic evaluation in CD1 mice showed that YM-08 crossed the BBB and maintained a brain/plasma (B/P) value of ∼0.25 for at least 18 h. Together, these studies suggest that YM-08 is a promising scaffold for the development of Hsp70 inhibitors suitable for use in the CNS.

Prediction of tide levels is one of the important problems in determining the schedule making of activities or constructions in coastal and oceanic area. Accurate predictions of tide levels could not be obtained without a long length (about one month or more) of tide measurements by conventional methods. A method of using a short length (a few days) of tide measurements to predict tide levels over a longer time is proposed in the present paper. In the method, a harmonic tide level model is used to predict tide levels. The parameters of the tide level model, that is, the amplitudes of the harmonic components, are estimated by Kalman filtering technique using a few-day tide record with the assumption of known angular frequencies. The proposed model is then applied to the short-term tide level prediction of the Kaohsiung Harbor, Taiwan. As a result, the tide levels predicted by the proposed method are in good agreement with the observed data.

Purpose: The purpose of this study was to compare the time needed to reach a specified temperature and the efficiency of two warming methods-warm cotton blankets and a radiant warmer-for hypothermia patients in a postanesthetic care unit (PACU) after spinal surgery.Design: This study was conducted according to a quasi-experimental design. Data were collected from a medical referral center in northern Taiwan. A total of 130 post-spinal surgery patients with hypothermia were recruited in the study.Methods: Of the 130 patients in the PACU, 65 were warmed by the radiant warmer (group R); whereas the other 65 patients were warmed by warm cotton blankets (group B). Tympanic temperature was measured for each patient every 10 min until it reached 36°C in the PACU. Analysis of covariance and generalized estimating equation regression analysis were performed to compare the time needed to reach a specified temperature and the efficiency of the two wanning methods, respectively.Findings: Both groups were similar in their baseline chara cteristics. After adjusting for temperature upon arrival at the PACU, group R needed a significantly shorter time for rewarming to 36°C than group B (F [1, 125] = 58.17, p Conclusions: Using the radiant warmer may be a more efficient method than providing warm cotton blankets for wanning post-spinal surgery hypothermia patients in the PACU.Clinical Relevance: For hospitals that are unable to use forced-air warming to warm postsurgical hypothermia patients in the PACU, the radiant warmer is a more efficient device to rewarm patients.Key wordsHypothermia, postoperative, spinal surgery, warming methodSurgical patient hypothermia is a common phenomenon that may occur before, during, or after operations. Numerous preoperative, intraoperative, and postoperative hypothermia-related research studies have been conducted since 1980. Studies have reponed that postoperative hypothermia, defined as having a core temperature of less than 36°C, occurs in 20% to 60% of all patients (Defina & Lincoln, 1998; Vaughan, Vaughan, & Cork, 1981). Spinal surgery involves a wide spectrum of procedures during which the spinal cord, nerve roots, and blood vessels are frequently at risk for injury (Gonzalez, Jeyanandarajan, Hansen, Zada, &* Hsieh, 2009). For patients undergoing spinal surgery, intraoperative active warming is difficult, since they are placed in the prone position, which allows only the legs to be covered with warming devices (Murat, Berniere, & Constant, 1994). The following questions thus arise: what can the clinical staff do to decrease this inadvertent hypothermia after spinal surgery, and which of the devices readily available in hospitals are the most effective for rewarming these patients in the PACU?Literature ReviewThermoregulatory MechanismsHumans are capable of maintaining homeostasis under fluctuating environmental conditions. For example, under normal circumstances, body temperature usually remains between 36.5°C and 37.5°C, with most changes being within I0C (Cooper, 2006). The center for regulation of body temperature is situated in the hypothalamus, which is responsible for the precise balancing of heat production and conservation, heat loss, and redistribution of heat via three major thermoregulatory mechanisms: vasoconstriction, shivering, and sweating (Wagner, 2006a). In surgical patients undergoing general or major regional anesthesia, hypothermia develops immediately after the induction of anesthesia because heat is redistributed from the center of the body to the periphery (Wagner, 2006b). …

Purpose: The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism.Experimental Design: Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro. A nonobese diabetic/severe combined immunodeficient xenograft model was used to determine whether sulforaphane could target breast CSCs in vivo, as assessed by Aldefluor assay, and tumor growth upon cell reimplantation in secondary mice. The potential mechanism was investigated using Western blotting analysis and β-catenin reporter assay.Results: Sulforaphane (1-5 μmol/L) decreased aldehyde dehydrogenase–positive cell population by 65% to 80% in human breast cancer cells (P < 0.01) and reduced the size and number of primary mammospheres by 8- to 125-fold and 45% to 75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for 2 weeks reduced aldehyde dehydrogenase–positive cells by >50% in nonobese diabetic/severe combined immunodeficient xenograft tumors (P = 0.003). Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after the reimplantation of primary tumor cells into the secondary mice (P < 0.01). Western blotting analysis and β-catenin reporter assay showed that sulforaphane downregulated the Wnt/β-catenin self-renewal pathway.Conclusions: Sulforaphane inhibits breast CSCs and downregulates the Wnt/β-catenin self-renewal pathway. These findings support the use of sulforaphane for the chemoprevention of breast cancer stem cells and warrant further clinical evaluation. Clin Cancer Res; 16(9); 2580–90. ©2010 AACR.

Purpose of the research Oral cancer is a common malignant disease in Taiwan. The purpose of this prospective follow-up study was to identify the changes in quality of life for newly diagnosed oral cancer patients during the acute stage. Methods and sample Subjects were recruited from the outpatient department (OPD) in a medical center located in the northern part of Taiwan. 22 subjects completed both the EORTC QLQ-C30 and the EORTC QLQ-H&N35 at diagnosis, postoperative discharge, and the first postoperative follow-up. In addition, 91% of the subjects received surgery only as their main treatment. Key results During the three assessments, as measured by the EORTC QLQ-C30, subjects reported that their physical function was much better at diagnosis than at both postoperative discharge and first postoperative follow-up. Their role functioning was much better at diagnosis than at postoperative discharge. Nevertheless, subjects reported better emotional functioning at the first postoperative follow-up than at the other two points of assessment. Only less financial difficulty was reported in the first postoperative follow-up than at diagnosis and postoperative discharge. For QLQ-H&N35, subjects reported that several symptoms (i.e., swallowing) were more severe at postoperative discharge than at diagnosis. Usage of nutritional supplements at first postoperative follow-up was higher than that at diagnosis. Conclusion Newly diagnosed oral cancer patients reported significant changes in certain domains of both the EORTC QLQ-C30 and QLQ-H&N35. Health professionals need to identify the pattern of changes and to provide supportive care to these new oral cancer patients throughout the treatment process, especially during the planning of discharge.

(−)-Epigallocatechin-3-gallate [(−)-EGCG], the most abundant polyphenolic catechin in green tea, showed chemoprevention and anticancer activities. (−)-EGCG was reported to bind to the C-terminal domain of heat shock protein 90 (Hsp90). The purpose of this study is to investigate (−)-EGCG as a novel Hsp90 inhibitor to impair Hsp90 super-chaperone complex for simultaneous down-regulation of oncogenic proteins in pancreatic cancer cells. MTS assay showed that (−)-EGCG exhibited anti-proliferative activity against pancreatic cancer cell line Mia Paca-2 in vitro with IC50 below 50 μM. (−)-EGCG increased caspase-3 activity up to 3-fold in a time- and concentration-dependent manner. Western Blotting analysis demonstrated that (−)-EGCG induced down-regulation of oncogenic Hsp90 client proteins by approximately 70%~95%, including Akt, Cdk4, Raf-1, Her-2, and pERK. Co-immunoprecipitation showed that (−)-EGCG decreased the association of co-chaperones p23 and Hsc70 with Hsp90 by more than 50%, while it had little effect on the ATP binding to Hsp90. Proteolytic fingerprinting assay confirmed direct binding between (−)-EGCG and the Hsp90 C-terminal domain. These data suggest that the binding of (−)-EGCG to Hsp90 impairs the association of Hsp90 with its co-chaperones, thereby inducing degradation of Hsp90 client proteins, resulting anti-proliferating effects in pancreatic cancer cells.

About 8,000 people die every year in Taiwan as a result of nosocomial infection. Clinically, there is a high possibility for patients to contract nosocomial infection if medical equipment is not completely sterilized. In order to provide care and safety to patients in the operating room, increase management effectiveness and efficiency, and to reduce equipment operating costs, a project was developed to improve operating room management through data collection and analysis. A computerized barcode operational system for packages of surgical instruments was developed and executed throughout an entire operating room. The results showed that average time spent searching for surgical instruments decreased by 2,872 minutes (47.8hrs/month), 150% of the target figure; computerized monitoring of equipment expiration dates reduced total cost by 29.2% abnormal recognition of equipment tags was reduced to 0%. This project is the first one of its kind in the world.

High-throughput screening of National Cancer Institute libraries of synthetic and natural compounds identified the vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4 H-cyclohepta[ b]thiophene-3-carboxamide (NSC727447) and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (NSC727448) as inhibitors of the ribonuclease H (RNase H) activity of HIV-1 and HIV-2 reverse transcriptase (RT). A Yonetani-Theorell analysis demonstrated that NSC727447, and the active-site hydroxytropolone RNase H inhibitor beta-thujaplicinol were mutually exclusive in their interaction with the RNase H domain. Mass spectrometric protein footprinting of the NSC727447 binding site indicated that residues Cys280 and Lys281 in helix I of the thumb subdomain of p51 were affected by ligand binding. Although DNA polymerase and pyrophosphorolysis activities of HIV-1 RT were less sensitive to inhibition by NSC727447, protein footprinting indicated that NSC727447 occupied the equivalent region of the p66 thumb. Site-directed mutagenesis using reconstituted p66/p51 heterodimers substituted with natural or non-natural amino acids indicates that altering the p66 RNase H primer grip significantly affects inhibitor sensitivity. NSC727447 thus represents a novel class of RNase H antagonists with a mechanism of action differing from active site, divalent metal-chelating inhibitors that have been reported.

A series of cyclic hydrocarbons were introduced to react with V(+) and Ta(+) using a pulsed beam expansion source in a time-of-flight mass spectrometer. The third-row metal Ta(+) displayed high reactivity in dehydrogenation to form benzyne complexes, whereas benzene complexes were the terminal products for V(+). M(+)-C(6)H(6) (M(+) = V(+) and Ta(+)) and Ta(+)-C(6)H(4) were selected to perform the photodissociation experiments. In contrast to the V(+) fragment formation via simple cleavage of the V(+)-C(6)H(6) bond, a photoinduced loss of C(2)H(2) occurred in both the Ta(+)-C(6)H(6) and Ta(+)-C(6)H(4) complexes. Plausible explanations involved in the formation of Ta(+)-C(6)H(6) and Ta(+)-C(6)H(4) complexes are given for observing such photo-induced dissociation. The observed photodissociation in Ta(+)-C(6)H(6) is analogous to the dissociative process previously investigated in metal ion-molecule reactions. The photodissociation spectrum of Ta(+)-C(6)H(4) was obtained by recording the appearance of Ta(+)-C(4)H(2) as a function of wavelength and yielded a dissociation energy of 91 +/- 1 kcal mol(-1).

Background STAT3 activation is frequently detected in breast cancer and this pathway has emerged as an attractive molecular target for cancer treatment. Recent experimental evidence suggests ALDH-positive (ALDH(+)), or cell surface molecule CD44-positive (CD44(+)) but CD24-negative (CD24(-)) breast cancer cells have cancer stem cell properties. However, the role of STAT3 signaling in ALDH(+) and ALDH(+)/CD44(+)/CD24(-) subpopulations of breast cancer cells is unknown. Methods and results We examined STAT3 activation in ALDH(+) and ALDH(+)/CD44(+)/CD24(-) subpopulations of breast cancer cells by sorting with flow cytometer. We observed ALDH-positive (ALDH(+)) cells expressed higher levels of phosphorylated STAT3 compared to ALDH-negative (ALDH(-)) cells. There was a significant correlation between the nuclear staining of phosphorylated STAT3 and the expression of ALDH1 in breast cancer tissues. These results suggest that STAT3 is activated in ALDH(+) subpopulations of breast cancer cells. STAT3 inhibitors Stattic and LLL12 inhibited STAT3 phosphorylation, reduced the ALDH(+) subpopulation, inhibited breast cancer stem-like cell viability, and retarded tumorisphere-forming capacity in vitro. Similar inhibition of STAT3 phosphorylation, and breast cancer stem cell viability were observed using STAT3 ShRNA. In addition, LLL12 inhibited STAT3 downstream target gene expression and induced apoptosis in ALDH(+) subpopulations of breast cancer cells. Furthermore, LLL12 inhibited STAT3 phosphorylation and tumor cell proliferation, induced apoptosis, and suppressed tumor growth in xenograft and mammary fat pad mouse models from ALDH(+) breast cancer cells. Similar in vitro and tumor growth in vivo results were obtained when ALDH(+) cells were further selected for the stem cell markers CD44(+) and CD24(-). Conclusion These studies demonstrate an important role for STAT3 signaling in ALDH(+) and ALDH(+)/CD44(+)/CD24(-) subpopulations of breast cancer cells which may have cancer stem cell properties and suggest that pharmacologic inhibition of STAT3 represents an effective strategy to selectively target the cancer stem cell-like subpopulation.

The natural product sulforaphane (SF) has demonstrated efficacy against multiple forms of cancers and cancer stem cells. However, it is unclear what are the molecular targets for sulforaphane to inhibit breast cancer stem cells and how efficacy varies among four subtypes of breast cancers. In vitro assay showed that sulforaphane preferentially inhibited triple negative (TNBC) breast cancers, but did not show any efficacy to inhibit Her2+ breast cancer cells (even at >100 uM). However, when Her2+ breast cancer cells (with PTEN deletion) developed resistance to trastuzumab, sulforaphane showed more than 20-fold higher activity. Low concentration of sulforaphane (1 uM) also preferentially eliminates breast cancer stem cells from triple negative breast cancers. Her2+ breast cancer cells (with PTEN deletion and long term treatment of trastuzumab) induced resistance to trastuzumab and increase breast cancer stem cell populations by activating a positive feedback loop of IL-6 and NF-kB. Luciferase reporter assay and immunostaining showed that sulforaphane (1 uM) disrupted NF-kB translocation from cytosol to nucleus and inhibited its activity. Sulforaphane (1 uM) also inhibited endogenous IL-6 production by 50%. Sulforaphane (50 mg/kg, adjuvant therapy) reduced tumor formation rate by 70% and inhibit tumor volume by more than 90% of trastuzumab resistant Her2+ breast cancers in mouse fat pad. These data suggest that sulforaphane inhibits trastuzumab-resistant Her2+ breast cancers and breast cancer stem cells by disrupting NF-kB and IL6 positive feedback loop. Citation Format: Joseph Burnett, Hasan Korkaya, Bryan Newman, Sarah Conley, Jamie Connarn, Lichao Sun, Hsiu-Fang Lee, Maria Ouzounova, Max Wicha, Duxin Sun. Natural product sulforaphane selectively inhibits breast cancer stem cells in basal and trastuzumab resistant Her2+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 913. doi:10.1158/1538-7445.AM2013-913

Gene expression analysis predicted strong activation of HDACs, MYC and NF-kappaB with potential sensitivities to vorinostat in breast cancer stem cells. Vorinostat was subsequently confirmed to inhibit mammosphere formation of the ALDH+ subpopulation of SUM159. In the present study, we conducted microarray experiments with RNA extracts from stem cells (ALDH+) and non-stem cell (ALDH-) populations of SUM159 in the absence or presence of 1uM vorinostat for 12h and 24h. The action of vorinostat was modeled by a series of computational tools integrating chemical genomics, gene signatures, gene promoters, microRNAs, pathways and gene networks. In the stem-cell population (ALDH+ SUM159), promoter and gene signature analysis revealed that MYC and NF-kappaB were strongly down-regulated by vorinostat at 12h and more prominently at 24h. MicroRNAs predicted to be most likely down-regulated by vorinostat at 12h were known transcriptionally regulated by either MYC or NF-kappaB. Furthermore, Notch1 and its ligand JAG2 were identified as key factors in modulating MYC activities in response to vorinostat. The predicted MYC down-regulation by vorinostat was confirmed by western blot and RT-PCR and NF-kappaB down-regulation by luciferase reporter assay. Other pathways such as beta-catenin and SRC were not significantly modulated by vorinostat. Surprisingly, the RAS pathway was activated by vorinostat with up-regulation of a RAS-activation gene signature, over-expression of KRAS/MEK/ERK and potential down-regulation of let-7, a KRAS targeting microRNA. In addition, epithelial-to-mesenchymal transition (EMT) was predicted to be activated by vorinostat with up-regulation of an EMT gene signature (TGFB1, SNAIL, SLUG, TWIST, ZEB1, ZEB2, alpha-SMA, FN1, VIM, N-cadherin etc.) and potential down-regulation of miR-200, an EMT antagonizing microRNA. Activation of RAS and EMT could render drug resistance in bCSCs. In the non-stem cell population (ALDH- SUM159), vorinostat down-regulated MYC and NF-kappaB at 12h but to a lesser extent at 24h. Unlike the ALDH+ cells, the RAS pathway was down-regulated at both 12h and 24h with no significant change in EMT. In summary, vorinostat exhibited differential activities in the stem cell and non-stem cell populations of SUM159 with prominent down-regulation of MYC and NF-kappaB, and divergent activities in RAS and EMT. A gene network was constructed to model the dynamics of vorinostat action in bCSCs. Further investigations were warranted including potential drug combinations. The computational framework proved complementary to the wet-lab approaches and capable of providing guidance in therapeutic discovery in targeting breast cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-100. doi:1538-7445.AM2012-LB-100

Although conventional chemotherapies eliminate differentiated cancer cells in the bulk of tumors, they are ineffective against cancer stem cells (CSCs), which initiate tumors and result in cancer recurrence. The purpose of this study is to investigate the efficacy of HDAC inhibition by SAHA on breast CSCs through epigenetic modifications in cancer stem cells. Two different breast cancer cell lines with basal (SUM159) and luminal (MCF7) subtypes were used in this study. In order to examine HDAC mediated CSC regulation, we utilized a number of in vitro and in vivo CSC assays including tumorsphere formation, Aldefluor assay, CD44+/CD24- phenotype and mouse xenografts. Breast cancer stem cells (CSC) were monitored after treatment of different concentrations of SAHA (0.5-2µM). The ability of HDAC inhibitor to suppress the self-renewal capability of CSCs was evaluated by tumorsphere assay from a single Aldefluor-positive cell in a 96-well Ultra-low attachment plate under the suspension condition. The tumorsphere formation rate was used to evaluate the self-renewal capability of CSCs. The mouse xenograft model bearing with SUM159 cells and primary breast tumors (MC1) was used to test the inhibition of SAHA on CSCs and impairment of their self renewal in vivo. Microarray gene expression analysis was performed to elucidate molecular mechanisms of HDAC underlying the CSC inhibition, following the treatment of SAHA. SAHA reduced SUM159 Aldefluor-positive cells in a concentration-dependent manner with significant reduction (>50%) at 1µM. SAHA dramatically reduced the CSC population (CD44+/CD24 low) by 90% in MCF7 cells. Since CSCs are able to expand its population through the self-renewal, a CSC-targeting drug to inhibit both self-renewal and to eliminate CSCs is highly desired. Tumorsphere formation assay showed that SAHA (0.5µM) reduced the tumorsphere formation rate by 77%. In addition, the sustaining tumorsphere reductions (∼80%) in second and third passages in the absence of SAHA suggest the the impaired self-renewal capability of breast CSCs by SAHA is not repairable. Furthermore, the size of SAHA-treated tumorspheres was substantially smaller than that of the control, suggesting that SAHA also inhibited the proliferation of progenitor cells. In SUM159 tumor xenograft model, SAHA significantly inhibited the tumor growth by 45% and 84% in SUM159 and MC1 tumor xenografts, respectively, compared to the vehicle-treated group. SAHA reduced Aldefluor-positive cells in SUM159 and MC1 tumors by 50-90% following 2-week treatment. Tumor reimplantation showed that SAHA was able to abolish the tumor engraftment ability of cells derived from drug-treated mice in secondary mice. These data suggest that SAHA was able to target breast CSCs in vitro and in vivo. SAHA not only diminished the CSC population but also attenuated their self-renewal ability of the residual CSCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3354. doi:10.1158/1538-7445.AM2011-3354

Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. The purpose of this study was to evaluate sulforaphane, a naturally occurring dietary compound from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs as well as to elucidate the potential mechanisms of its effect. Aldefluor and mammosphere formation assays were used to assess the effect of sulforaphane on breast CSCs in vitro. A NOD/SCID xenograft model was employed to determine the efficacy of sulforaphane in targeting breast CSCs in vivo. The potential mechanism of sulforaphane was investigated utilizing Western blotting and β-catenin reporter assays. The results showed that sulforaphane (1∼5 µM) decreased aldehyde dehydrogenase (ALDH)-positive cell population by 65%∼80% in human breast cancer cell line (P < 0.01), and reduced the size and number of primary mammospheres by 8∼125-fold and 50%∼75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for two weeks reduced ALDH-positive cells by more than 50% in tumors (P = 0.003). Furthermore, sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor re-growth in secondary mice (P < 0.01). Western blotting showed that sulforaphane down-regulated the Wnt/β-catenin self-renewal pathway. These data suggest that sulforaphane targets breast CSCs through the down-regulation of the Wnt/β-catenin pathway as a potential mechanism. These findings provide a scientific rationale for use of sulforaphane and potentially broccoli/broccoli sprout dietary interventions for breast cancer chemoprevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4271.