Determination of the Mechanisms that Cause Sarcopenia through cDNA Microarray.

BACKGROUND: Sarcopenia, the aging-related deterioration of skeletal muscle, is a disease that is directly associated with quality of life. Given the trend of an increasing aging population worldwide, the prevention of aging-related diseases such as sarcopenia has become ever more important and urgent. OBJECTIVE: To identify potential therapeutic targets for this disease. METHODS: we used a bioinformatics approach of combining cDNA microarray analysis and protein-protein interaction prediction. RESULTS: We found 673 significant differentially expressed genes (128 upregulated and 545 downregulated) in sarcopenia patients of over 60 years of age. Most of the upregulated genes were involved in metabolic processes such as the PPAR signaling pathway. In particular, FABP4, PLIN1, and ADIPOQ were related to fatty acid and lipid metabolism. Some of the downregulated genes were located in the mitochondrial matrix. Additionally, through the protein interaction network analysis, we found two key molecules (MAP1LC3B and HSP90AB1) that were associated with autophagy. CONCLUSIONS: These results suggest that mitochondrial dysfunction and lipid metabolism are associated with sarcopenia.

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.

BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. PATIENTS AND METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology. RESULTS: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC. CLINICALTRIALSGOV REGISTRY: NCT01295827.

Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia.

Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 × 10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2) and 17 mg/m(2)) were explored dosing on a weekly schedule × 3 with 1 week off (4-week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.

Higher serum beta2-microglobulin levels are associated with better survival in chronic hemodialysis patients: a reverse epidemiology.

AIMS: beta2-Microglobulin (beta2-M) has been considered a surrogate marker of putative mid-molecular weight (MW) uremic toxins, compounds difficult to dialyze by low-flux dialysis membranes. This study was performed to evaluate the relationship between serum beta2-M and survival of chronic hemodialysis (CHD) patients and the association of beta2-M levels and factors associated with mortality. METHODS: Part I of this study is a retrospective cohort evaluation that determined the relationship between beta2-M and mortality, and Part II is a cross-sectional study that evaluated the relationship between beta2-M and factors associated with mortality. Laboratory parameters, including beta2-M, albumin, prealbumin, creatinine, blood urea nitrogen (BUN), high-sensitivity C-reactive protein (hs-CRP), lipid battery, KT/V, and normalized protein nitrogen appearance (nPNA), were reviewed in Part I and measured in Part II. Clinical and demographic data, including age, sex, duration of hemodialysis, presence of cardiovascular disease, and presence of diabetes mellitus, were also recorded. RESULTS: Part I: During the follow-up period of 5 years, there were 95 all-cause deaths among the 289 patients. Comparison of survivors and non-survivors indicated that serum beta2-M was higher in survivors (36.8 ± 12.3 vs. 32.6 ± 13.2 µg/ml, p = 0.009). Kaplan-Meier analysis indicated that all-cause mortality in the lower beta2-M group was significantly higher compared to the higher beta2-M group (p < 0.0001). Multivariate Cox regression analyses indicated elevated beta2-M levels were significantly associated with lower mortality rate (relative risk: 0.608; 95% CI: 0.37 to 0.99; p = 0.046). Part II: The mean serum beta2-M concentration was 37.1 ± 14.4 µg/ml. Univariate analysis indicated that beta2-M was positively correlated with nPNA, duration of HD, BMI, and the concentrations of creatinine, albumin, BUN, and hs-CRP, but was negatively correlated with HDL-C concentration. Multiple regression analysis indicated that levels of nPNA (p < 0.001), duration of hemodialysis (p < 0.001), creatinine (p < 0.001), albumin (p = 0.006), BUN (p = 0.011), and HDL-C (p = 0.038) were independently associated with serum beta2-M concentration. CONCLUSION: Our results showed that higher serum beta2-M levels are associated with better survival in CHD patients and that nutritional status might be an independent predictor of serum beta2-M concentration in these patients.

[Recent advances in Saccharomyces boulardii research]. / Progrès récents dans la recherche sur Saccharomyces boulardii.

This review summarizes the probiotic mechanisms of action of Saccharomyces boulardii (S. boulardii) against inflammatory and non-inflammatory diarrheal conditions. S. boulardii is distributed in lyophilized form in many countries and used for the prevention of diarrhea in children and adults, including Clostridium difficile (C. difficile) associated infection. The main mechanisms of action of S. boulardii include inhibition of activities of bacterial pathogenic products, trophic effects on the intestinal mucosa, as well as modification of host signaling pathways involved in inflammatory and non-inflammatory intestinal diseases. S. boulardii inhibits production of pro-inflammatory cytokines by inhibiting main regulators of inflammation, including nuclear factor κB (NF-κB), and mitogen-activated protein kinases (MAP kinases), ERK1/2 and p38, but stimulates production of anti-inflammatory molecules such as peroxisome proliferator-activated receptor-gamma (PPAR-γ). Moreover, S. boulardii suppresses bacterial infection by inhibiting adhesion and/or overgrowth of bacteria, produces a serine protease that cleaves C. difficile toxin A, and stimulates antibody production against this toxin. Furthermore, S. boulardii may interfere with pathogenesis of Inflammatory Bowel Disease (IBD) by acting on T cells and acts in diarrheal conditions by improving the fecal biostructure in patients with diarrhea. These diverse mechanisms exerted by S. boulardii provide molecular clues for its effectiveness in diarrheal diseases and intestinal inflammatory conditions with an inflammatory component.

Functional changes in a novel uracil-DNA glycosylase determined by mutational analyses.

Uracil-DNA glycosylase (UDG) is a ubiquitous enzyme found in bacteria and eukaryotes, which removes uracil residues from DNA strands. Methanococcus jannaschii UDG (MjUDG), a novel monofunctional glycosylase, contains a helix-hairpin-helix (HhH) motif and Gly/Pro rich loop (GPD region), which is important for catalytic activity; it shares these features with other glycosylases such as endonuclease III. First, to examine the role of two conserved amino acid residues (Asp150 and Tyr152) in the HhH-GPD region of MjUDG, mutant MjUDG proteins were constructed, in which Asp 150 was replaced with either Glu or Trp (D150E and D150W), Tyr152 was replaced with either Glu or Asn (Y152E and Y152N). Mutant D150W completely lacked DNA glycosylase activity, whereas D150E displayed reduced activity of about 70% of the wild type value. However, the mutants Y152E and Y152N retained unchanged levels of UDG activity. We also replaced Glu132 in the HhH motif with a lysine residue equivalent to Lys120 in endonuclease III. This mutation converted the enzyme into a bifunctional glycosylase/AP lyase capable of both removing uracil at a glycosylic bond and cleaving the phosphodiester backbone at an AP site. Mutant E132K catalyzes a beta-elimination reaction at the AP site via uracil excision and forms a Schiff base intermediate in the form of a protein-DNA complex.

Vulnerability of Korean water resources to climate change and population growth.

Freshwater availability is affected by changes in climate and growth. We assessed the freshwater vulnerability for five major Korean river basins for 2015 and 2030. We used a regional climate model based on the IPCC SRES A2 scenario, US Geological Survey's Precipitation Rainfall Simulation Model, and population and industrial growth scenarios for impact assessment. The model simulation results suggest increasing spatial and temporal variations of water stress for the basins that are already developed. While freshwater is more vulnerable to growth scenarios than the climate change scenario, climate change alone could decrease mean annual runoff by 10% in four major river basins by 2030. As the first national assessment of climate change, we suggest possible adaptive water resource management and policy strategies for reducing climate related risks in Korea.

Engineering RENTA, a DNA prime-MVA boost HIV vaccine tailored for Eastern and Central Africa.

For the development of human immunodeficiency virus type 1 (HIV-1) vaccines, traditional approaches inducing virus-neutralizing antibodies have so far failed. Thus the effort is now focused on elicitation of cellular immunity. We are currently testing in clinical trials in the United Kingdom and East Africa a T-cell vaccine consisting of HIV-1 clade A Gag-derived immunogen HIVA delivered in a prime-boost regimen by a DNA plasmid and modified vaccinia virus Ankara (MVA). Here, we describe engineering and preclinical development of a second immunogen RENTA, which will be used in combination with the present vaccine in a four-component DNA/HIVA-RENTA prime-MVA/HIVA-RENTA boost formulation. RENTA is a fusion protein derived from consensus HIV clade A sequences of Tat, reverse transcriptase, Nef and gp41. We inactivated the natural biological activities of the HIV components and confirmed immunogenicities of the pTHr.RENTA and MVA.RENTA vaccines in mice. Furthermore, we demonstrated in mice and rhesus monkeys broadening of HIVA-elicited T-cell responses by a parallel induction of HIVA- and RENTA-specific responses recognizing multiple HIV epitopes.

A feminist critique of research on cancer pain.

A number of studies on cancer pain have been conducted but the researchers rarely considered gender and ethnic differences in cancer pain. In this article, nursing research on cancer pain is critiqued from a feminist perspective, and directions for future nursing research are proposed. A total of 82 nursing articles published in the United States were retrieved through MEDLINE and MELVYL data retrieval systems, and analyzed and critiqued in terms of four basic elements of research from a feminist perspective (bias as resources, dependability, credibility and adequacy, and intersubjectivity). In this article, the critique is presented with four themes that may provide reasons why nursing research on cancer pain rarely incorporated gender and ethnic differences: absence of participants' own views and experiences, androcentrism and ethnocentrism, lack of consideration on contextual factors, and distant relationships between researchers and research participants. To overcome the limitations, six critical elements including gender and ethnic sensitivity, avoidance of distorted views, respectfor participants' own views and interests, trust and openness, empowerment, and multiple methods are suggested to be incorporated in future nursing research on cancer pain.

Physical activity of Korean immigrant women in the U.S.: needs and attitudes.

The purpose of the study was to explore women's own needs for and attitudes toward physical activity among Korean immigrant women in the US using feminist approach and transition theory. This was a cross-sectional study consisting of quantitative and qualitative phases. Using convenience sampling methods, 54 Korean immigrant women were recruited for the quantitative phase, and 15 women among them were recruited for the qualitative phase. Questionnaires and semi-structured interviews were used to collect data. The data were analyzed using descriptive and inferential statistics and thematic analysis. The findings indicated that the women's needs for and attitudes toward physical activity were influenced by the contexts of their culture and immigration, and deeply associated with the women's daily experiences. Some implications for future research and nursing practice are proposed based on the findings.

Women's work and symptoms during midlife: Korean immigrant women.

PURPOSE: To describe how Korean immigrant women tend to describe their work experiences within their daily lives and how they relate their work to the symptoms experienced during midlife. DESIGN: Cross-sectional study using methodological triangulation. Using a convenience sampling method, 119 Korean immigrant women were recruited for the quantitative phase, and 21 among the 119 women were recruited for the qualitative phase. Data were collected using both questionnaires and in-depth interviews. The data were analyzed using descriptive and inferential statistics and thematic analysis. FINDINGS AND DISCUSSIONS: The symptoms that the women experienced during midlife were influenced by their work experience, which was complicated by their cultural heritage, gender issues embedded in their daily lives, and immigration transition. IMPLICATIONS: Complexities and diversities in women's work need to be incorporated in menopausal studies.

A feminist critique on the use of the Internet in nursing research.

With the increasing use of the Internet, the importance of incorporating this new technology in nursing research increases. Yet nursing has been slow in adopting this new technology as a research method, and the use of the Internet in nursing research rarely has been discussed and critiqued. In this article, use of the Internet in nursing research is analyzed and critiqued from a feminist perspective. The analysis indicates that use of the Internet in research frequently brings about selection biases because of a limited pool of potential participants, it usually does not provide contextual data on research encounters, it might not uncover women's subjective experiences under marginalized situations, and it tends to raise power issues related to the relationships between researchers and participants. Despite the limitations, use of the Internet in research provides better communication channels for research participants, more flexibility in time and place of data collection, and less expense for data collection. Based on the critique, feminist challenges for future use of the Internet in nursing research are proposed.

Apoptotic activity of novel bile acid derivatives in human leukemic T cells through the activation of caspases.

The therapeutic efficacies of bile acids, such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA), have been widely demonstrated in various liver diseases, suggesting that they might protect hepatocytes against common mechanisms of liver damage. Although they have been shown to prevent apoptotic cell death in certain cell lines, we have previously reported that a novel derivative (HS-1030) of UDCA significantly inhibited cell growth and induced apoptosis in cancer cells. To develop more effective agents, we synthesized several derivatives, named HS-1183, HS-1199 and HS-1200, based on the structure of UDCA and CDCA, and investigated them for anti-proliferative activity in Jurkat cells, a human leukemic T cell line. Whereas UDCA and CDCA had no significant effects on the growth of Jurkat cells in the concentration range tested, both HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed only a weak inhibitory activity. Furthermore, chromatin condensation, DNA ladder formation and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) were observed after treatment of novel bile acids, indicating the occurrence of apoptotic cell death, which was associated with down-regulation of caspase-3 and -8. The apoptotic manifestations such as PARP cleavage and DNA fragmentation were abolished in the presence of the tripeptide caspase inhibitor zVAD-fmk or the specific caspase-3 inhibitor DEVD-fmk. Our data thus demonstrate that novel bile acid derivatives-induced apoptosis of leukemic T cells is dependent on caspase activation.

Novel bile acid derivatives induce apoptosis via a p53-independent pathway in human breast carcinoma cells.

We have compared the anti-proliferative effects of ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA) and their derivatives, HS-1183, HS-1199 and HS-1200, on MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53) cells. While UDCA and CDCA exhibited no significant effect, their novel derivatives inhibited the proliferation of both cell lines in a concentration-dependent manner, concomitant with apoptotic nuclear changes and the increase of a sub-G1 population and DNA fragmentation. Furthermore, we also observed an increase in the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2 and cleavages of lamin B and poly(ADP-ribose) polymerase (PARP) in MCF-7 and MDA-MB-231 cells. Cell cycle related proteins, cyclin D1 and D3, as well as retinoblastoma protein (pRb) were down-regulated, while the level of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) was increased in both cancer cells after treatment with novel bile acids. These findings suggest that these cytotoxic effects of novel bile acid derivatives on human breast carcinoma cells were mediated via apoptosis through a p53-independent pathway.

Nursing research on physical activity: a feminist critique.

Studies on physical activity have rarely included women as research participants, and have been mainly conducted among Western populations. In this paper, nursing research on women's physical activity is analyzed and critiqued using a feminist perspective that respects and values women's own experiences and their diversities. An extensive literature search was conducted using computerized data retrieval systems and 47 empirical studies published in nursing literature were selected and analyzed. The critique is presented with three main themes emerged from the analysis: (a) "without considering women's own experiences"; (b) "implicit androcentric and ethnocentric assumptions"; (c) "without meaningful interactions". Based on the analysis, future directions for nursing research on physical activity are proposed.

An international imperative for gender-sensitive theories in women's health.

PURPOSE: To propose gender-sensitive theories as a future direction for theoretical development of women's health. Few theories pertain to women's health and illness experiences, with gender issues embedded in social, cultural, and historical contexts. ORGANIZING CONSTRUCT: Significance, definition, and philosophical bases of gender-sensitive theories. FINDINGS: Six major components should be incorporated in the development of gender-sensitive theories: (a) gender as a major feature, (b) women's own words and experiences, (c) nature of women's experiences, (d) theorists' perspectives, (e) contexts, and (f) guidelines for actions. CONCLUSIONS: We believe that the development of gender-sensitive theories in nursing could enable researchers to transcend androcentric and ethnocentric views on women's health, decrease gender inequity in health care, enhance women's well being, and ultimately contribute to knowledge development in nursing.

Inhibition of cell growth and telomerase activity of breast cancer cells in vitro by retinoic acids.

The effects of retinoic acid (RA) and its analogs, all-trans RA, 9-cis RA and 13-cis RA, were investigated in human breast cancer MCF-7 cells and immortalized breast epithelial cell line MCF-10A. RA inhibited the telomerase activity of MCF-7 cells in a wide range of concentrations. RA at 10 microM also inhibited the growth of MCF-7 cells in a time-dependent manner. However, no significant growth inhibition was found between untreated control and RA-treated MCF-10A cells. Moreover, a marked inhibition of telomerase activity by RA was detected early in MCF-7 cells (after 24 h of RA treatment), which was preceded by a reduction of hTERT mRNA expression (after 12 h of RA treatment). However, MCF-10A cells showed a reduction of telomerase activity and down-regulation of hTERT after 4 days of RA treatment. Simultaneous changes in hTERT mRNA expression and telomerase activity were found for MCF-10A cells. The expressions of hTR and hTEP1 telomerase component genes were not changed after RA treatment. These results indicate that the anti-breast cancer activity of RA could be mediated by its ability to down-regulate the expression of hTERT telomerase gene.

Experiencing transitions: an emerging middle-range theory.

Changes in health and illness of individuals create a process of transition, and clients in transition tend to be more vulnerable to risks that may in turn affect their health. Uncovering these risks may be enhanced by understanding the transition process. As a central concept of nursing, transition has been analyzed, its components identified, and a framework to articulate and to reflect the relationship between these components has been defined. In this article, the previous conceptual analysis of transitions is extended and refined by drawing on the results of five different research studies that have examined transitions using an integrative approach to theory development. The emerging middle-range theory of transitions consists of types and patterns of transitions, properties of transition experiences, facilitating and inhibiting conditions, process indicators, outcome indicators, and nursing therapeutics. The diversity, complexity, and multiple dimensionality of transition experiences need to be further explored and incorporated in future research and nursing practice related to transitions.