RNATACs: Multispecific small molecules targeting RNA by induced proximity.

RNA-targeting small molecules (rSMs) have become an attractive modality to tackle traditionally undruggable proteins and expand the druggable space. Among many innovative concepts, RNA-targeting chimeras (RNATACs) represent a new class of multispecific, induced proximity small molecules that act by chemically bringing RNA targets into proximity with an endogenous RNA effector, such as a ribonuclease (RNase). Depending on the RNA effector, RNATACs can alter the stability, localization, translation, or splicing of the target RNA. Although still in its infancy, this new modality has the potential for broad applications in the future to treat diseases with high unmet need. In this review, we discuss potential advantages of RNATACs, recent progress in the field, and challenges to this cutting-edge technology.

Clinical information and guidance shared via a patient infotainment system can reduce hospital stay and maintain 2 medical quality for total knee arthroplasty: A single-blinded quasi-randomised controlled trial.

BACKGROUND: The demand for total knee arthroplasty is increasing worldwide. Optimising results and meeting patients' expectations are more challenging than before, because the length of hospitalisation has markedly reduced and the standard care processes have been accelerated. We incorporated an interactive patient infotainment system into the standard clinical pathway for total knee arthroplasty in the hope of improving patients' length of stay. OBJECTIVES: To analyse whether incorporation of an interactive infotainment system reduced the length of stay and improved the quality of medical care (in terms of number of medical orders and emergency room returns). DESIGN: A prospective, quasi-randomised controlled trial. PARTICIPANTS AND SETTING: Data of 86 patients hospitalised for a unilateral total knee arthroplasty at a medical centre in Taiwan were analysed. METHODS: From January 2017 to July 2017, 86 patients who underwent unilateral total knee arthroplasty and were cared for under a standard clinical pathway were included. The study group (41 patients) had access to electronic programs and video demonstrations related to health literacy, physical therapy, home care and precautions following total knee arthroplasty via a patient infotainment system, while the control group (45 patients) did not. Hospital course, quality indices, in-hospital medical costs, returns to the emergency room and readmission at 30 or 90 days were analysed and compared between the two groups of patients. RESULTS: The study group had a shorter length of stay (4.4 vs. 4.8 days, mean differences [MD] = -0.37, 95% CI -0.71 to -0.03, p = 0.026) and fewer medical orders (109 vs 111 orders, MD = -1.86, 95% confidence intervals (CI) -3.58 to -0.15, p = 0.047) as compared with the control group. The incidences of emergency room return and readmission to the hospital at 30 or 90 days were comparable between the two groups. No difference in the total medical cost was found between the two groups, with only the cost of laboratory tests in the study group being significantly lower than that in the control group ($144 vs. $163, MD = -21.7, 95% CI -41.0 to -2.25, p = 0.007). CONCLUSIONS: The incorporation of a patient infotainment system into the standard clinical pathway for total knee arthroplasty can efficiently reduce the length of hospital stay and maintain the quality of medical care. Further studies on improvement of patient medical literacy with the help of the infotainment system would be of interest in order to improve clinical practice and patient satisfaction. REGISTRATION NUMBER: NCT03788798 TWEETABLE ABSTRACT: A patient infotainment system can reduce hospital stay and maintain medical quality for total knee arthroplasty.

Health education and competency scale: Development and testing.

AIMS AND OBJECTIVE: To develop a tool for measuring competency in conducting health education and to evaluate its psychometric properties in a population of entry-level nurses. BACKGROUND: Until now, no generic instrument has been developed specifically for measuring competency in health education, which is an essential competency for nurses. Existing scales are either insufficient for psychometric evaluation or are designed specifically for senior nurses. To evaluate curricula and courses designed for entry-level nurses, educators require an instrument for measuring improvement in core competency from baseline to determine whether the minimum level of ability has been achieved. DESIGN: Item development for the survey instrument used for data collection in this study was based on the results of a literature review. METHODS: The self-evaluated Health Education Competency Scale developed in this study was used to survey 457 nursing students at two nursing schools and 165 clinical nurses at a medical centre in south Taiwan in 2016. The participants were randomly divided into two equal groups. One group was analysed by exploratory factor analysis with varimax rotation, and one group was analysed by confirmatory factor analysis. RESULTS: Factor analysis yielded a four-factor (assessment, pedagogy, motivation and empowerment) solution (18 items) that accounted for 75.9% of the variance. CONCLUSION: The total scale and subscales had good reliabilities and construct validity coefficients. For measuring competency in entry-level nurses, the Health Education Competency Scale had a good data fit and sound psychometric properties. RELEVANCE TO CLINICAL PRACTICE: The proposed scale can be used to assess health education competency for college nursing students and practising nurses. Furthermore, it can provide educators with valuable insight into the minimum competencies required for entry-level nurses to deliver quality health care to clients and can guide them in the practice of client-based teaching.

Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers.

Human mitochondrial pyrroline-5-carboxylate reductase (PYCR) is a house-keeping enzyme that catalyzes the reduction of Δ1-pyrroline-5-carboxylate to proline. This enzymatic cycle plays pivotal roles in amino acid metabolism, intracellular redox potential and mitochondrial integrity. Here, we hypothesize that PYCR1 might be a novel prognostic biomarker and therapeutic target for breast cancer. In this study, breast cancer tissue samples were obtained from Zhejiang University (ZJU set). Immunohistochemistry analysis was performed to detect the protein level of PYCR1, and Kaplan-Meier and Cox proportional analyses were employed in this outcome study. The prognostic significance and performance of PYCR1 mRNA were validated on 13 worldwide independent microarray data sets, composed of 2500 assessable breast cancer cases. Our findings revealed that both PYCR1 mRNA and protein expression were significantly associated with tumor size, grade and invasive molecular subtypes of breast cancers. Independent and pooled analyses verified that higher PYCR1 mRNA levels were significantly associated with poor survival of breast cancer patients, regardless of estrogen receptor (ER) status. For in vitro studies, inhibition of PYCR1 by small-hairpin RNA significantly reduced the growth and invasion capabilities of the cells, while enhancing the cytotoxicity of doxorubicin in breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative). Further population study also validated that chemotherapy significantly improved survival in early-stage breast cancer patients with low PYCR1 expression levels. Therefore, PYCR1 might serve as a prognostic biomaker for either ER-positive or ER-negative breast cancer subtypes and can also be a potential target for breast cancer therapy.

Exploring Discrepancies in Perceived Nursing Competence Between Postgraduate-Year Nurses and Their Preceptors.

BACKGROUND: Postgraduate clinical training programs improve the core competence of nurses. How postgraduate-year (PGY) nurses perceive their clinical competence and their preceptors' perceptions may affect program effectiveness. This study compared the perspectives of clinical competencies of PGY nurses engaged in a residency program in Taiwan with their preceptors' perspectives. METHOD: A cross-sectional study was conducted at a medical center in Taiwan. The Nursing Competence Questionnaire was used to obtain data from 99 pairs of PGY nurses and preceptors. RESULTS: PGY nurses' scores were higher than their preceptors' for communication, patient education, and management competencies (p <.05). Preceptors with more years of clinical experience exhibited greater assessment discrepancies for clinical care, communication, patient education, research awareness, and overall competence (p <.05). CONCLUSION: Preceptor development courses should be grounded in a strong pedagogical framework. An assessment tool with explicit behavioral indicators would be needed for objective evaluation from both perspectives. J Contin Educ Nurs. 2017;48(4):190-196.

Predictor of Self-Perceived Nursing Competency Among New Nurses in Taiwan.

The aim of this article is to identify the factors that predict self-perceived nursing competency among new nurses in Taiwan. This quantitative cross-sectional survey was performed with a convenience sample of 105 new nurses. Data were collected with questionnaires. Multiple linear regression showed perceived benefit of preceptor policies to nursing capacity and age accounted for 21.1% of the variance in dependent variables for self-perceived nursing competency importance. Satisfaction with current preceptor, satisfaction with current nursing job, and participation in interprofessional education conferences accounted for 22% of the variance in dependent variables for self-perceived nursing competency adequacy. The results could be a reference to design nursing education curricula that improve clinical training and retention of new nurses. J Contin Educ Nurs. 2017;48(3):129-137.

Longitudinal Analysis of Severe Anxiety Symptoms in the Last Year of Life Among Patients With Advanced Cancer: Relationships With Proximity to Death, Burden, and Social Support.

BACKGROUND: Temporal changes in the prevalence of anxiety disorders/symptoms for patients with cancer at the end of life (EOL) remain unclear. This study was undertaken to describe changes in the prevalence of severe anxiety symptoms and to identify its correlates in the last year of life for patients with cancer. METHODS: A convenience sample of 325 patients with cancer was followed until death. Severe anxiety symptoms were identified as anxiety subscale scores of 11 or greater on the Hospital Anxiety and Depression Scale. Longitudinal changes in and correlates of severe anxiety symptoms were examined from demographics, disease-related characteristics, disease burden, perceived burden to others, and social support using multivariate logistic regression modeling with generalized estimating equations. RESULTS: The prevalence of severe anxiety symptoms increased as death approached (18.6%, 21.9%, 26.7%, and 33.4% at 181-365, 91-180, 31-90, and 1-30 days before death, respectively). However, after controlling for covariates, this temporal increase was not significant. The prevalence of severe anxiety symptoms was not associated with fixed demographics and disease-related characteristics, except for diagnosis and metastatic status, but was significantly higher in patients with cancer with high physical symptom distress, severe depressive symptoms, high perceived burden to others, and strong perceived social support. CONCLUSIONS: Severe anxiety symptoms were not associated with time proximity to death per se but were related to factors modifiable by high-quality EOL care. Clinicians may decrease the likelihood of severe anxiety symptoms at EOL by adequately managing physical and depressive symptoms and lightening perceived burden to others for patients strongly connected with their social network to improve their psychological well-being.

[The Association of the Disturbed Degree of Job Stressful Events, Physical Data and Quality of Life in Allied Personnel of Outpatient Department].

BACKGROUND: Interactions between allied personnel and patients that occur during the provision of healthcare services may affect patient evaluations of the quality of medical care received. The many patients served and stresses faced every day by allied personnel may disturb their physical and psychological health and negatively affect their quality of life. PURPOSE: The aim of this study is to explore the association among stressful job-related events, physical data, and quality of life in allied personnel who work in outpatient departments. METHODS: This cross-sectional study used structured questionnaires and physical-data tests. The participants were recruited from a medical center in southern Taiwan. A total of 141 valid questionnaires were obtained, with a response rate of 88.1%. RESULTS: Larger differences between systolic and diastolic blood pressure and greater disturbed feelings toward stressful events were both associated with poorer quality of life in participants. Furthermore, the internal stressors related to the context of job and hospital sites impacted the quality of life of participants more than the external stressors related to patients or outsiders. CONCLUSIONS: The results of the present study may serve as a reference for nursing departments in medical institutions to establish contingency strategies for job stressful events and to enhance and promote the quality of life of allied personnel working in outpatient departments.

PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress.

Ribonucleotide reductase small subunit B (RRM2B) is a stress response protein that protects normal human fibroblasts from oxidative stress. However, the underlying mechanism that governs this function is not entirely understood. To identify factors that interact with RRM2B and mediate anti-oxidation function, large-scale purification of human Flag-tagged RRM2B complexes was performed. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1, PYCR2) were identified by mass spectrometry analysis as components of RRM2B complexes. Silencing of both PYCR1 and PYCR2 by expressing short hairpin RNAs induced defects in cell proliferation, partial fragmentation of the mitochondrial network, and hypersensitivity to oxidative stress in hTERT-immortalized human foreskin fibroblasts (HFF-hTERT). Moderate overexpression of RRM2B, comparable to stress-induced level, protected cells from oxidative stress. Silencing of both PYCR1 and PYCR2 completely abolished anti-oxidation activity of RRM2B, demonstrating a functional collaboration of these metabolic enzymes in response to oxidative stress.

Do-not-resuscitate orders and related factors among family surrogates of patients in the emergency department.

PURPOSE: The purpose of this study was to investigate the prevalence of do-not-resuscitate (DNR) orders and to identify relevant factors influencing the DNR decision-making process by patients' surrogates in the emergency department (ED). METHODS: A prospective, descriptive, and correlational research design was adopted. A total of 200 surrogates of cancer or non-cancer terminal patients, regardless of whether they signed a DNR order, were recruited as subjects after physicians of the emergency department explained the patient's conditions, advised on withholding medical treatment, and provided information on palliative care to all surrogates. RESULTS: Of the 200 surrogates, 23 % signed a DNR order for the patients. The demographic characteristics of patients and surrogates, the level of understanding of DNR orders, and factors of the DNR decision had no significant influence on the DNR decision. However, greater severity of disease (odds ratio (OR) = 1.38; 95 % confidence interval (CI) = 0.95-1.74), physician's initiative in discussing with the families (OR = 1.42; 95 % CI = 1.21-1.84), and longer length of hospital stay (OR = 1.06; 95 % CI = 1.03-1.08) were contributing factors affecting patient surrogates' DNR decisions. CONCLUSIONS: The findings of this study indicated that surrogates of patients who were more severe in disease condition, whose physicians initiated the discussion of palliative care, and who stayed longer in hospital were important factors affecting the surrogates' DNR decision-making. Therefore, early initiation of DNR discussions is suggested to improve end-of-life care.

RRM2B-Mediated Regulation of Mitochondrial Activity and Inflammation under Oxidative Stress.

RRM2B is a critical ribonucleotide reductase (RR) subunit that exists as p53-inducible and p53-dependent molecule. The p53-independent regulation of RRM2B has been recently studied, and FOXO3 was identified as a novel regulator of RRM2B. However, the p53-independent regulation of RRM2B, particularly under oxidative stress, remains largely unknown. In this study, we investigated the role of RRM2B underoxidative stress-induced DNA damage and further examined the regulation of mitochondrial and inflammatory genes by RRM2B. Our study is the first to report the critical role of RRM2B in mitochondrial homeostasis and the inflammation signaling pathway in a p53-independent manner. Furthermore, our study provides novel insights into the role of the RR in inflammatory diseases.

Tumor suppressor FOXO3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients.

The role of Ribonucleotide reductase (RR) subunits in different cancers has been intensively studied in our laboratory. RRM2B was identified as a p53-inducible RR subunit that involves in various critical cellular mechanisms such as cell cycle regulation, DNA repair and replication, and mitochondrial homeostasis, etc. However, little is known about the p53-independent regulation of RRM2B in cancer pathology. In this study, we discovered tumor suppressor FOXO3 as the novel regulator of RRM2B. FOXO3 directly bound to and transcriptionally activated the promoter of RRM2B, and induced the expression of RRM2B at RNA and protein levels. Moreover, Overexpression of RRM2B and/or FOXO3 inhibited the proliferation of cancer cells. The cancer tissue microarray data also demonstrated a strong correlation between the co-expression of FOXO3 plus RRM2B and increased disease survival and reduced recurrence or metastasis in lung cancer patients. Our results suggest a novel regulatory control of RRM2B function, and imply the importance of FOXO signaling pathway in DNA replication modulation. This study provides the first time evidence that RRM2B is transcriptionally and functionally regulated independent of p53 pathway by FOXO3, and it establishes that FOXO3 and RRM2B could be used as predictive biomarkers for cancer progression.

Reciprocal regulation of autophagy and dNTP pools in human cancer cells.

Ribonucleotide reductase (RNR) plays a critical role in catalyzing the biosynthesis and maintaining the intracellular concentration of 4 deoxyribonucleoside triphosphates (dNTPs). Unbalanced or deficient dNTP pools cause serious genotoxic consequences. Autophagy is the process by which cytoplasmic constituents are degraded in lysosomes to maintain cellular homeostasis and bioenergetics. However, the role of autophagy in regulating dNTP pools is not well understood. Herein, we reported that starvation- or rapamycin-induced autophagy was accompanied by a decrease in RNR activity and dNTP pools in human cancer cells. Furthermore, downregulation of the small subunit of RNR (RRM2) by siRNA or treatment with the RNR inhibitor hydroxyurea substantially induced autophagy. Conversely, cancer cells with abundant endogenous intracellular dNTPs or treated with dNTP precursors were less responsive to autophagy induction by rapamycin, suggesting that autophagy and dNTP pool levels are regulated through a negative feedback loop. Lastly, treatment with si-RRM2 caused an increase in MAP1LC3B, ATG5, BECN1, and ATG12 transcript abundance in xenografted Tu212 tumors in vivo. Together, our results revealed a previously unrecognized reciprocal regulation between dNTP pools and autophagy in cancer cells.

RRM2B suppresses activation of the oxidative stress pathway and is up-regulated by p53 during senescence.

RRM2B is the DNA damage-inducible small subunit of ribonucleotide reductase, the rate-limiting enzyme in de novo deoxyribonucleoside triphosphate synthesis. Although RRM2B is implicated in DNA repair and the maintenance of mitochondrial DNA content, the regulation and function of RRM2B in senescence have not been previously established. Here, we show that RRM2B is highly induced in a p53-dependent manner during senescence in primary human fibroblast IMR90 cells and is expressed at higher levels in senescent precancerous human prostatic intraepithelial neoplasm lesions compared to adjacent normal prostate glands. Paradoxically, silencing RRM2B expression leads to an increase in the level of reactive oxygen species, mitochondrial membrane depolarization, and premature senescence in a p38MAPK- and p53-dependent manner in young fibroblasts. Consistently, induction of senescence is accelerated in Rrm2b deficient mouse embryo fibroblasts. Our data demonstrate that RRM2B is induced by stress signals prior to the onset of senescence and prevents premature oxidative stress-induced senescence.

Ribonucleotide reductase subunit p53R2 regulates mitochondria homeostasis and function in KB and PC-3 cancer cells.

Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes de novo conversion of ribonucleotide 5'-diphosphates to the corresponding 2'-deoxynucleotide, essential for DNA synthesis and replication. The mutations or knockout of RR small subunit, p53R2, results in the depletion of mitochondrial DNA (mtDNA) in human, implying that p53R2 might play a critical role for maintaining mitochondrial homeostasis. In this study, siRNA against p53R2 knockdown approach is utilized to examine the impact of p53R2 depletion on mitochondria and to derive underlying mechanism in KB and PC-3 cancer cells. Our results reveal that the p53R2 expression not only positively correlates with mtDNA content, but also partakes in the proper mitochondria function, such as ATP synthesis, cytochrome c oxidase activity and membrane potential maintenance. Furthermore, overexpression of p53R2 reduces intracellular ROS and protects the mitochondrial membrane potential against oxidative stress. Unexpectedly, knockdown of p53R2 has a modest, if any, effect on mitochondrial and total cellular dNTP pools. Taken together, our study provides functional evidence that mitochondria is one of p53R2-targeted organelles and suggests an unexpected function of p53R2, which is beyond known RR function on dNTP synthesis, in mitochondrial homeostatic control.

Ribonucleotide reductase small subunit M2B prognoses better survival in colorectal cancer.

Ribonucleotide reductase subunit RRM2B (p53R2) has been reported to suppress invasion and metastasis in colorectal cancer (CRC). Here, we report that high levels of RRM2B expression are correlated with markedly better survival in CRC patients. In a fluorescence-labeled orthotopic mouse xenograft model, we confirmed that overexpression of RRM2B in nonmetastatic CRC cells prevented lung and/or liver metastasis, relative to control cells that did metastasize. Clinical outcome studies were conducted on a training set with 103 CRCs and a validation set with 220 CRCs. All participants underwent surgery with periodic follow-up to determine survivability. A newly developed specific RRM2B antibody was employed to carry out immunohistochemistry for determining RRM2B expression levels on tissue arrays. In the training set, the Kaplan-Meier and multivariate Cox analysis revealed that RRM2B is associated with better survival of CRCs, especially in stage IV patients (HR = 0.40; 95% CI = 0.18-0.86, P = 0.016). In the validation set, RRM2B was negatively related to tumor invasion (OR = 0.45, 95% CI = 0.19-0.99, P = 0.040) and lymph node involvement (OR = 0.48, 95% CI = 0.25-0.92, P = 0.026). Furthermore, elevated expression of RRM2B was associated with better prognosis in this set as determined by multivariate analyses (HR = 0.48, 95% CI = 0.26-0.91, P = 0.030). Further investigations revealed that RRM2B was correlated with better survival of CRCs with advanced stage III and IV tumors rather than earlier stage I and II tumors. Taken together, our findings establish that RRM2B suppresses invasiveness of cancer cells and that its expression is associated with a better survival prognosis for CRC patients.

p53R2 inhibits the proliferation of human cancer cells in association with cell-cycle arrest.

Deregulation of the expression of p53R2, a p53-inducible homologue of the R2 subunit of ribonucleotide reductase, has been found in various human cancer tissues; however, the roles p53R2 plays in cancer progression and malignancy remain controversial. In the present study, we examined changes in gene expression profiles associated with p53R2 in cancer cells, using the analysis of cDNA microarray. Gene set enrichment analysis identified that the gene set regulating cell-cycle progression was significantly enriched in p53R2-silencing human oropharyngeal carcinoma KB cells. Attenuation of p53R2 expression significantly reduced p21 expression and moderately increased cyclin D1 expression in both wild-type p53 cancer cells (KB and MCF-7) and mutant p53 cancer cells (PC3 and MDA-MB-231). Conversely, overexpression of p53R2-GFP resulted in an increase in the expression of p21 and decrease in the expression of cyclin D1, which correlated with reduced cell population in S-phase in vitro and suppressed growth in vivo. Furthermore, the MAP/ERK kinase inhibitor PD98059 partially abolished modulation of p21 and cyclin D1 expression by p53R2. Moreover, under the conditions of nonstress and adriamycin-induced genotoxic stress, attenuation of p53R2 in KB cells significantly increased phosphorylated H2AX, which indicates that attenuation of p53R2 may enhance DNA damage induced by adriamycin. Overall, our study shows that p53R2 may suppress cancer cell proliferation partially by upregulation of p21 and downregulation of cyclin D1; p53R2 plays critical roles not only in DNA damage repair but also in proliferation of cancer cells.

Efficient and directed Nano-LED emission by a complete elimination of transverse-electric guided modes.

A key to the success of solid-state lighting is an ultraefficient light extraction, ∼90%. Recent advances in nanotechnology, particularly in creating nanorods, present an unprecedented opportunity to manipulate optical modes at nanometer scales. Here, we report an optically pumped nanorod light-emitting diode (LED) with an ultrahigh extraction efficiency of 79% at λ = 460 nm without the use of either a back reflector or thin film technology. We demonstrated experimentally three key mechanisms for achieving high efficiency: guided mode-reduction, embedded quantum wells, and ultraefficient light out-coupling by the fundamental HE(11) mode. Furthermore, we show that size reduction at nanoscale represents a new degree-of-freedom for alternating and achieving a more directed LED emission.

Three-dimensional inverted photonic grating with engineerable refractive indices for broadband antireflection of terahertz waves.

Reduction of reflection is of great importance in optical spectroscopy to reduce interference and increase throughput. Here we demonstrate a three-dimensional inverted photonic grating device design using only one material-silicon. Enhanced transmission compared to planar silicon wafers is observed from 0.2 THz to over 7.3 THz for a device with a 15 µm period, which covers most of the terahertz band, and its relative 3 dB bandwidth (δf/f(c)) is a noteworthy 116.3%. Moreover, the device is polarization independent and can perform up to a large incident angle.

Large enhancement of light-extraction efficiency from optically pumped, nanorod light-emitting diodes.

We report a threefold enhancement of light-emission intensity at lambda=460 nm and a 16-fold extraction-efficiency enhancement measured from a 2D array of nanorod LEDs. The nano-LEDs are randomly arranged and have a typical rod diameter of 100-250 nm. From a combination of photoluminescence, reflectance, and excitation power-dependence measurements, we show that the enhanced emission is due mainly to modification of the extraction efficiency, and not to that of the internal efficiency. Furthermore, we show that the extraction enhancement originates from the randomness of the 2D array that scatters light efficiently into the air and the smallness of the nanorods that eliminates the guiding modes that trap light.