No Evidence of a Drug-Drug Interaction Between Letermovir (MK-8228) and Mycophenolate Mofetil

Introduction: Letermovir (MK-8228) is a potent, oncedaily inhibitor of the cytomegalovirus (CMV) terminase complex that is being developed for the prophylaxis of CMV infection in transplant patients. This study evaluated the pharmacokinetic interactions, safety, and tolerability of letermovir when coadministered in healthy subjects with mycophenolate mofetil (MMF), which is the morpholinoethyl ester prodrug of mycophenolic acid (MPA). Methods: This was an open-label trial in 14 healthy female subjects that explored the pharmacokinetic parameters of a single 1 g oral dose of MMF administered alone on Day 1 and coadministered on Day 12 with 480 mg oral once-daily letermovir given on Day 5 and from Day 8 continued through Day 16. Letermovir PK was assessed at single dose (Day 5) and at steady state on Day 12 (with MMF) and Day 16 (alone following MMF washout). Results: Coadministration of 480 mg qd letermovir at steady state with a single dose of 1 g of MMF had no effect on the pharmacokinetics of MPA. The MPA AUC0-inf and Cmax geometric mean ratios (GMRs) [90% confidence interval] for the comparison (MMF with letermovir/ MMF alone) were 1.08 [0.96, 1.21] and 0.96 [0.81, 1.13], respectively. Coadministration of a single dose of 1 g MMF with 480 mg qd letermovir at steady state had no clinically meaningful effect on the pharmacokinetics of letermovir, with AUC0-24 and Cmax GMR of 1.18 [1.04, 1.32] and 1.11 [0.93, 1.34], respectively. The letermovir geometric mean accumulation ratio (Day 16/Day 5) and 95% CI were 1.13 [0.90, 1.42] for AUC0-24 and 1.01 [ 0.79, 1.28] f or Cmax, indicating that accumulation of letermovir when administered as daily doses is minimal. All related AEs were reported as mild in severity and resolved. Conclusions: Multiple-dose administration of 480 mg letermovir daily with a single dose of 1 g MMF was generally well tolerated by the healthy subjects in this study. Coadministration of letermovir and MMF had no clinically meaningful effect on the PK of letermovir or MPA. Letermovir and MMF may be coadministered without dose adjustment

Obtaining Statistics of Turbulent Velocity from Astrophysical Spectral Line Data

Turbulence is a crucial component of dynamics of astrophysical fluids dynamics, including those of ISM, clusters of galaxies and circumstellar regions. Doppler shifted spectral lines provide a unique source of information on turbulent velocities. We discuss Velocity-Channel Analysis (VCA) and its offspring Velocity Coordinate Spectrum (VCS) that are based on the analytical description of the spectral line statistics. Those techniques are well suited for studies of supersonic turbulence. We stress that a great advantage of VCS is that it does not necessary require good spatial resolution. Addressing the studies of mildly supersonic and subsonic turbulence we discuss the criterion that allows to determine whether a traditional tool for such a research, namely, Velocity Centroids are dominated by density or velocity. We briefly discuss the use of higher order correlations as the means to study intermittency of turbulence. We discuss observational data available and prospects of the field.Comment: 12 pages, Invited Talk, Penetrating Bars Through Masks of Cosmic Dust, Pilanesberg National Park, South Afrika, 7 June-12 June 200

Lifetime economic impact of the burden of childhood stunting attributable to maternal psychosocial risk factors in 137 low/middle-income countries

Introduction: The first 1000 days of life is a period of great potential and vulnerability. In particular, physical growth of children can be affected by the lack of access to basic needs as well as psychosocial factors, such as maternal depression. The objectives of the present study are to: (1) quantify the burden of childhood stunting in low/middle-income countries attributable to psychosocial risk factors; and (2) estimate the related lifetime economic costs. Methods: A comparative risk assessment analysis was performed with data from 137 low/middle-income countries throughout Asia, Latin America and the Caribbean, North Africa and the Middle East, and sub-Saharan Africa. The proportion of stunting prevalence, defined as <-2 SDs from the median height for age according to the WHO Child Growth Standards, and the number of cases attributable to low maternal education, intimate partner violence (IPV), maternal depression and orphanhood were calculated. The joint effect of psychosocial risk factors on stunting was estimated. The economic impact, as reflected in the total future income losses per birth cohort, was examined. Results: Approximately 7.2 million cases of stunting in low/middle-income countries were attributable to psychosocial factors. The leading risk factor was maternal depression with 3.2 million cases attributable. Maternal depression also demonstrated the greatest economic cost at $14.5 billion, followed by low maternal education ($10.0 billion) and IPV ($8.5 billion). The joint cost of these risk factors was$29.3 billion per birth cohort. Conclusion: The cost of neglecting these psychosocial risk factors is significant. Improving access to formal secondary school education for girls may offset the risk of maternal depression, IPV and orphanhood. Focusing on maternal depression may play a key role in reducing the burden of stunting. Overall, addressing psychosocial factors among perinatal women can have a significant impact on child growth and well-being in the developing world

Momentum asymmetries as CP violating observables

Three body decays can exhibit CP violation that arises from interfering diagrams with different orderings of the final state particles. We construct several momentum asymmetry observables that are accessible in a hadron collider environment where some of the final state particles are not reconstructed and not all the kinematic information can be extracted. We discuss the complications that arise from the different possible production mechanisms of the decaying particle. Examples involving heavy neutralino decays in supersymmetric theories and heavy Majorana neutrino decays in Type-I seesaw models are examined.Comment: 20 pages, 9 figures. Clarifying comments and one reference added, matches published versio

Health literacy, health status, and healthcare utilization of Taiwanese adults: results from a national survey

Abstract Background Low health literacy is considered a worldwide health threat. The purpose of this study is to assess the prevalence and socio-demographic covariates of low health literacy in Taiwanese adults and to investigate the relationships between health literacy and health status and health care utilization. Methods A national survey of 1493 adults was conducted in 2008. Health literacy was measured using the Mandarin Health Literacy Scale. Health status was measured based on self-rated physical and mental health. Health care utilization was measured based on self-reported outpatient clinic visits, emergency room visits, and hospitalizations. Results Approximately thirty percent of adults were found to have low (inadequate or marginal) health literacy. They tended to be older, have fewer years of schooling, lower household income, and reside in less populated areas. Inadequate health literacy was associated with poorer mental health (OR, 0.57; 95% CI, 0.35-0.91). No association was found between health literacy and health care utilization even after adjusting for other covariates. Conclusions Low (inadequate and marginal) health literacy is prevalent in Taiwan. High prevalence of low health literacy is not necessarily indicative of the need for interventions. Systematic efforts to evaluate the impact of low health literacy on health outcomes in other countries would help to illuminate features of health care delivery and financing systems that may mitigate the adverse health effects of low health literacy.http://deepblue.lib.umich.edu/bitstream/2027.42/78252/1/1471-2458-10-614.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78252/2/1471-2458-10-614.pdfPeer Reviewe

SMART: Unique splitting-while-merging framework for gene clustering

Copyright @ 2014 Fa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Successful clustering algorithms are highly dependent on parameter settings. The clustering performance degrades significantly unless parameters are properly set, and yet, it is difficult to set these parameters a priori. To address this issue, in this paper, we propose a unique splitting-while-merging clustering framework, named “splitting merging awareness tactics” (SMART), which does not require any a priori knowledge of either the number of clusters or even the possible range of this number. Unlike existing self-splitting algorithms, which over-cluster the dataset to a large number of clusters and then merge some similar clusters, our framework has the ability to split and merge clusters automatically during the process and produces the the most reliable clustering results, by intrinsically integrating many clustering techniques and tasks. The SMART framework is implemented with two distinct clustering paradigms in two algorithms: competitive learning and finite mixture model. Nevertheless, within the proposed SMART framework, many other algorithms can be derived for different clustering paradigms. The minimum message length algorithm is integrated into the framework as the clustering selection criterion. The usefulness of the SMART framework and its algorithms is tested in demonstration datasets and simulated gene expression datasets. Moreover, two real microarray gene expression datasets are studied using this approach. Based on the performance of many metrics, all numerical results show that SMART is superior to compared existing self-splitting algorithms and traditional algorithms. Three main properties of the proposed SMART framework are summarized as: (1) needing no parameters dependent on the respective dataset or a priori knowledge about the datasets, (2) extendible to many different applications, (3) offering superior performance compared with counterpart algorithms.National Institute for Health Researc

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

Export of functional Streptomyces coelicolor alditol oxidase to the periplasm or cell surface of Escherichia coli and its application in whole-cell biocatalysis

Streptomyces coelicolor A3(2) alditol oxidase (AldO) is a soluble monomeric flavoprotein in which the flavin cofactor is covalently linked to the polypeptide chain. AldO displays high reactivity towards different polyols such as xylitol and sorbitol. These characteristics make AldO industrially relevant, but full biotechnological exploitation of this enzyme is at present restricted by laborious and costly purification steps. To eliminate the need for enzyme purification, this study describes a whole-cell AldO biocatalyst system. To this end, we have directed AldO to the periplasm or cell surface of Escherichia coli. For periplasmic export, AldO was fused to endogenous E. coli signal sequences known to direct their passenger proteins into the SecB, signal recognition particle (SRP), or Twin-arginine translocation (Tat) pathway. In addition, AldO was fused to an ice nucleation protein (INP)-based anchoring motif for surface display. The results show that Tat-exported AldO and INP-surface-displayed AldO are active. The Tat-based system was successfully employed in converting xylitol by whole cells, whereas the use of the INP-based system was most likely restricted by lipopolysaccharide LPS in wild-type cells. It is anticipated that these whole-cell systems will be a valuable tool for further biological and industrial exploitation of AldO and other cofactor-containing enzymes.

Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment

BACKGROUND: Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. METHODS: OT-I CTL were adoptively transferred to C57BL/6 mice 21 – 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. RESULTS: Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. CONCLUSIONS: Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several antigens when developing vaccine strategies for cancer

PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

Letter to the Edito