Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients

Background Modern immunosuppressive regimens after kidney transplantation usually use a combination of two or three agents of different classes to prevent rejection and maintain graft function. Most frequently, calcineurin‐inhibitors (CNI) are combined with corticosteroids and a proliferation‐inhibitor, either azathioprine (AZA) or mycophenolic acid (MPA). MPA has largely replaced AZA as a first line agent in primary immunosuppression, as MPA is believed to be of stronger immunosuppressive potency than AZA. However, treatment with MPA is more costly, which calls for a comprehensive assessment of the comparative effects of the two drugs. Objectives This review of randomised controlled trials (RCTs) aimed to look at the benefits and harms of MPA versus AZA in primary immunosuppressive regimens after kidney transplantation. Both agents were compared regarding their efficacy for maintaining graft and patient survival, prevention of acute rejection, maintaining graft function, and their safety, including infections, malignancies and other adverse events. Furthermore, we investigated potential effect modifiers, such as transplantation era and the concomitant immunosuppressive regimen in detail. Search methods We searched Cochrane Kidney and Transplant's Specialised Register (to 21 September 2015) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review. Selection criteria All RCTs about MPA versus AZA in primary immunosuppression after kidney transplantation were included, without restriction on language or publication type. Data collection and analysis Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random‐effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Main results We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported. MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death‐censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all‐cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy‐proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody‐treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta‐regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro‐emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures. Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue‐invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. Authors' conclusions MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue‐invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on

Long-distance remote comparison of ultrastable optical frequencies with 1e-15 instability in fractions of a second

We demonstrate a fully optical, long-distance remote comparison of independent ultrastable optical frequencies reaching a short term stability that is superior to any reported remote comparison of optical frequencies. We use two ultrastable lasers, which are separated by a geographical distance of more than 50 km, and compare them via a 73 km long phase-stabilized fiber in a commercial telecommunication network. The remote characterization spans more than one optical octave and reaches a fractional frequency instability between the independent ultrastable laser systems of 3e-15 in 0.1 s. The achieved performance at 100 ms represents an improvement by one order of magnitude to any previously reported remote comparison of optical frequencies and enables future remote dissemination of the stability of 100 mHz linewidth lasers within seconds.Comment: 7 pages, 4 figure

The Lotic Intersite Nitrogen Experiments: an example of successful ecological research collaboration

Collaboration is an essential skill for modern ecologists because it brings together diverse expertise, viewpoints, and study systems. The Lotic Intersite Nitrogen eXperiments (LINX I and II), a 17-y research endeavor involving scores of early- to late-career stream ecologists, is an example of the benefits, challenges, and approaches of successful collaborative research in ecology. The scientific success of LINX reflected tangible attributes including clear scientific goals (hypothesis-driven research), coordinated research methods, a team of cooperative scientists, excellent leadership, extensive communication, and a philosophy of respect for input from all collaborators. Intangible aspects of the collaboration included camaraderie and strong team chemistry. LINX further benefited from being part of a discipline in which collaboration is a tradition, clear data-sharing and authorship guidelines, an approach that melded field experiments and modeling, and a shared collaborative goal in the form of a universal commitment to see the project and resulting data products through to completion

Nitrate removal in stream ecosystems measured by 15N addition experiments: Total uptake

We measured uptake length of 15NO3− in 72 streams in eight regions across the United States and Puerto Rico to develop quantitative predictive models on controls of NO3− uptake length. As part of the Lotic Intersite Nitrogen eXperiment II project, we chose nine streams in each region corresponding to natural (reference), suburban-urban, and agricultural land uses. Study streams spanned a range of human land use to maximize variation in NO3− concentration, geomorphology, and metabolism. We tested a causal model predicting controls on NO3− uptake length using structural equation modeling. The model included concomitant measurements of ecosystem metabolism, hydraulic parameters, and nitrogen concentration. We compared this structural equation model to multiple regression models which included additional biotic, catchment, and riparian variables. The structural equation model explained 79% of the variation in log uptake length (SWtot). Uptake length increased with specific discharge (Q/w) and increasing NO3− concentrations, showing a loss in removal efficiency in streams with high NO3− concentration. Uptake lengths shortened with increasing gross primary production, suggesting autotrophic assimilation dominated NO3− removal. The fraction of catchment area as agriculture and suburban-urban land use weakly predicted NO3− uptake in bivariate regression, and did improve prediction in a set of multiple regression models. Adding land use to the structural equation model showed that land use indirectly affected NO3− uptake lengths via directly increasing both gross primary production and NO3− concentration. Gross primary production shortened SWtot, while increasing NO3− lengthened SWtot resulting in no net effect of land use on NO3− removal

The Deuterium to Hydrogen Ratio in the Water that Formed the Yellowknife Bay Mudstones in Gale Crater

A suite of isotope ratios of light elements in the present martian atmosphere (13C/12C, 15N/14N, 18O/16O, 38Ar/36Ar, and D/H) are all substantially enriched in the heavy element suggesting atmospheric loss to space over the past billions of years with preferential loss of the lighter isotope from each pair. In situ measurements from MSL's Sample Analysis at Mars (SAM) instrument [e.g. 1,2,3] have considerably refined previous measurements from the Viking mass spectrometers [e.g. 4], from remote spectroscopic observations [e.g. 5,6], and from martian meteorite studies [e.g. 7,8]. The persistence of habitable environments such as the ancient Yellowknife Bay lake recently revealed by measurements from the Curiosity rover [9] depends on the surface temperatures and the duration of an atmosphere thicker than that at present. Current and planned measurements from orbit with the Mars Express and MAVEN missions respectively intend to study the processes of atmospheric escape including solar wind interaction, sputtering, thermal escape, and dissociative recombination, and determine or refine the current rate of atmospheric loss caused by these and other mechanisms. The goal of these programs is to understand the physical processes sufficiently well so that robust extrapolations over the past billions of years can be made D/H is measured by both the Tunable Laser Spectrometer (TLS) and the Quadrupole Mass Spectrometer (QMS) of the SAM suite. to predict the atmospheric and surface conditions on early Mars. However, the study of the history of martian atmospheric evolution will be greatly facilitated if we are able to also directly measure the isotopic composition of volatiles captured in rocks that are representative of the ancient atmosphere. To date, D/H is one of the most promising candidates for this study since water is the most abundant volatile thermally released from the Yellowknife Bay phylosilicates discovered by the SAM and CheMin experiments of MSL and it

Novel epigenetic network biomarkers for early detection of esophageal cancer

BACKGROUND: Early detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity. RESULTS: Here we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett's Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status. CONCLUSIONS: Given our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum, a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation

A One Health overview, facilitating advances in comparative medicine and translational research.

Table of contentsA1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O'ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O'BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man's best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman

Author Correction: A Database of Snow on Sea Ice in the Central Arctic Collected during the MOSAiC expedition

Correction to: Scientific Data, published online 22 June 2023 The original version showed the wrong image for Figure 3, with the image for Figure 4 used for both. This has been corrected in the pdf and HTML versions of the article, with the correct version of Figure 3 replacing the duplicated figure. The dates in the figure captions were also incorrect and have been amended as follows: Figure 3 caption: “from 2019-10-25 - 2020-07-30” modified to “from 2019-10-25 - 2020-05-15” Figure 4 caption: “from 2020-02-25 - 2020-07-30” modified to “from 2020-06-13 - 2020-07-30”

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Funding Information: We thank Dr. David James, Dr. Frederick Lang, Dr. Cameron Brennan, and Dr. Harley Kornblum for GBM-PDX neurospheres. We thank Dr. Karen Arden for continuous support and critical evaluation of the results. We thank Dr. Robert Davis, Dr. German Gomez, Dr. Tiffany Taylor, Dr. Rachel Reed, Dr. Melissa Mcalonis, and Dr. Sora Lee for technical support. In memory of Rosa Lupo. This work was supported by the Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society (F.B.F. and P.S.M.), R01-NS080939 (F.B.F.), the James S. McDonnell Foundation (F.B.F.), the National Cancer Institute (2T32CA009523-29A1) (A.H.T), and 1RO1NS097649-01 (C.C.C.). C.Z. was partially supported by an American-Italian Cancer Foundation post-doctoral research fellowship. F.L. received a Gao Feng Gao Yuan Scholarship Award. T.C.G., A.K.S., P.S.M., W.K.C., and F.B.F. receive salary and additional support from the Ludwig Institute for Cancer Research. Publisher Copyright: © 2017 Zanca et al.In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.publishersversionPeer reviewe