Acute Kidney Injury Following Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma in a Kidney Transplant Recipient

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a newer and effective therapeutic option approved for patients with relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Acute kidney injury is a complication of CAR T-cell therapy that can result in kidney failure. In most cases, it is thought to be related to hemodynamic changes due to cytokine release syndrome. Kidney biopsy in this clinical scenario is usually not performed. We report on a kidney transplant recipient in his 40s who developed a posttransplant lymphoproliferative disorder of B-cell origin refractory to conventional treatments and received anti-CD19 CAR T-cell therapy as compassionate treatment. Beginning on day 12 after CAR T-cell infusion, in the absence of clinical symptoms, a progressive decline in estimated glomerular filtration rate of the kidney graft occurred. A subsequent allograft biopsy showed mild tubulointerstitial lymphocyte infiltrates, falling into a Banff borderline-changes category and resembling an acute immunoallergic tubulointerstitial nephritis. Neither CAR T cells nor lymphomatous B cells were detected within the graft cellular infiltrates, suggesting an indirect mechanism of kidney injury. Although kidney graft function partially recovered after steroid therapy, the posttransplant lymphoproliferative disorder progressed and the patient died 7 months later

The Feasibility of performing resistance exercise with acutely ill hospitalized older adults

BACKGROUND: For older adults, hospitalization frequently results in deterioration of mobility and function. Nevertheless, there are little data about how older adults exercise in the hospital and definitive studies are not yet available to determine what type of physical activity will prevent hospital related decline. Strengthening exercise may prevent deconditioning and Pilates exercise, which focuses on proper body mechanics and posture, may promote safety. METHODS: A hospital-based resistance exercise program, which incorporates principles of resistance training and Pilates exercise, was developed and administered to intervention subjects to determine whether acutely-ill older patients can perform resistance exercise while in the hospital. Exercises were designed to be reproducible and easily performed in bed. The primary outcome measures were adherence and participation. RESULTS: Thirty-nine ill patients, recently admitted to an acute care hospital, who were over age 70 [mean age of 82.0 (SD= 7.3)] and ambulatory prior to admission, were randomized to the resistance exercise group (19) or passive range of motion (ROM) group (20). For the resistance exercise group, participation was 71% (p = 0.004) and adherence was 63% (p = 0.020). Participation and adherence for ROM exercises was 96% and 95%, respectively. CONCLUSION: Using a standardized and simple exercise regimen, selected, ill, older adults in the hospital are able to comply with resistance exercise. Further studies are needed to determine if resistance exercise can prevent or treat hospital-related deterioration in mobility and function

Creatine Monohydrate and Conjugated Linoleic Acid Improve Strength and Body Composition Following Resistance Exercise in Older Adults

Aging is associated with lower muscle mass and an increase in body fat. We examined whether creatine monohydrate (CrM) and conjugated linoleic acid (CLA) could enhance strength gains and improve body composition (i.e., increase fat-free mass (FFM); decrease body fat) following resistance exercise training in older adults (>65 y). Men (N = 19) and women (N = 20) completed six months of resistance exercise training with CrM (5g/d)+CLA (6g/d) or placebo with randomized, double blind, allocation. Outcomes included: strength and muscular endurance, functional tasks, body composition (DEXA scan), blood tests (lipids, liver function, CK, glucose, systemic inflammation markers (IL-6, C-reactive protein)), urinary markers of compliance (creatine/creatinine), oxidative stress (8-OH-2dG, 8-isoP) and bone resorption (Ν-telopeptides). Exercise training improved all measurements of functional capacity (P<0.05) and strength (P<0.001), with greater improvement for the CrM+CLA group in most measurements of muscular endurance, isokinetic knee extension strength, FFM, and lower fat mass (P<0.05). Plasma creatinine (P<0.05), but not creatinine clearance, increased for CrM+CLA, with no changes in serum CK activity or liver function tests. Together, this data confirms that supervised resistance exercise training is safe and effective for increasing strength in older adults and that a combination of CrM and CLA can enhance some of the beneficial effects of training over a six-month period. Trial Registration. ClinicalTrials.gov NCT0047390

Coastal ocean and shelf-sea biogeochemical cycling of trace elements and isotopes: lessons learned from GEOTRACES

Continental shelves and shelf seas play a central role in the global carbon cycle. However, their importance with respect to trace element and isotope (TEI) inputs to ocean basins is less well understood. Here, we present major findings on shelf TEI biogeochemistry from the GEOTRACES programme as well as a proof of concept for a new method to estimate shelf TEI fluxes. The case studies focus on advances in our understanding of TEI cycling in the Arctic, transformations within a major river estuary (Amazon), shelf sediment micronutrient fluxes and basin-scale estimates of submarine groundwater discharge. The proposed shelf flux tracer is 228-radium (T1/2 = 5.75 yr), which is continuously supplied to the shelf from coastal aquifers, sediment porewater exchange and rivers. Model-derived shelf 228Ra fluxes are combined with TEI/ 228Ra ratios to quantify ocean TEI fluxes from the western North Atlantic margin. The results from this new approach agree well with previous estimates for shelf Co, Fe, Mn and Zn inputs and exceed published estimates of atmospheric deposition by factors of approximately 3–23. Lastly, recommendations are made for additional GEOTRACES process studies and coastal margin-focused section cruises that will help refine the model and provide better insight on the mechanisms driving shelf-derived TEI fluxes to the ocean. This article is part of the themed issue ‘Biological and climatic impacts of ocean trace element chemistry’

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

BACKGROUND: This study was performed to test the hypothesis that expression of small heat shock protein Hsp-27 is, at diagnosis, a reliable predictive biomarker of clinically aggressive prostate cancer. METHODS: A panel of tissue microarrays constructed from a well-characterised cohort of 553 men with conservatively managed prostate cancer was stained immunohistochemically to detect Hsp-27 protein. Hsp-27 expression was compared with a series of pathological and clinical parameters, including outcome. RESULTS: Hsp-27 staining was indicative of higher Gleason score (P7, the presence of Hsp-27 retained its power to independently predict poor clinical outcome (P<0.002). Higher levels of Hsp-27 staining were almost entirely restricted to cancers lacking ERG rearrangements (chi2 trend=31.4, P<0.001), although this distribution did not have prognostic significance. INTERPRETATION: This study has confirmed that, in prostate cancers managed conservatively over a period of more than 15 years, expression of Hsp-27 is an accurate and independent predictive biomarker of aggressive disease with poor clinical outcome (P<0.001). These findings suggest that apoptotic and cell-migration pathways modulated by Hsp-27 may contain targets susceptible to the development of biologically appropriate chemotherapeutic agents that are likely to prove effective in treating aggressive prostate cancers

Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells

Post-transcriptional modification of RNA nucleosides occurs in all living organisms. Pseudouridine, the most abundant modified nucleoside in non-coding RNAs, enhances the function of transfer RNA and ribosomal RNA by stabilizing the RNA structure. Messenger RNAs were not known to contain pseudouridine, but artificial pseudouridylation dramatically affects mRNA function—it changes the genetic code by facilitating non-canonical base pairing in the ribosome decoding centre. However, without evidence of naturally occurring mRNA pseudouridylation, its physiological relevance was unclear. Here we present a comprehensive analysis of pseudouridylation in Saccharomyces cerevisiae and human RNAs using Pseudo-seq, a genome-wide, single-nucleotide-resolution method for pseudouridine identification. Pseudo-seq accurately identifies known modification sites as well as many novel sites in non-coding RNAs, and reveals hundreds of pseudouridylated sites in mRNAs. Genetic analysis allowed us to assign most of the new modification sites to one of seven conserved pseudouridine synthases, Pus1–4, 6, 7 and 9. Notably, the majority of pseudouridines in mRNA are regulated in response to environmental signals, such as nutrient deprivation in yeast and serum starvation in human cells. These results suggest a mechanism for the rapid and regulated rewiring of the genetic code through inducible mRNA modifications. Our findings reveal unanticipated roles for pseudouridylation and provide a resource for identifying the targets of pseudouridine synthases implicated in human disease.American Cancer Society (Robbie Sue Mudd Kidney Cancer Research Scholar Grant RSG-13-396-01-RMC)National Institutes of Health (U.S.) (GM094303)National Institutes of Health (U.S.) (GM081399)American Cancer Society. New England Division (Ellison Foundation Postdoctoral Fellowship)American Cancer Society (Postdoctoral Fellowship PF-13-319-01-RMC)National Institutes of Health (U.S.) (Pre-doctoral Training Grant T32GM007287

From Global to Local and Vice Versa: On the Importance of the 'Globalization' Agenda in Continental Groundwater Research and Policy-Making.

Groundwater is one of the most important environmental resources and its use continuously rises globally for industrial, agricultural, and drinking water supply purposes. Because of its importance, more knowledge about the volume of usable groundwater is necessary to satisfy the global demand. Due to the challenges in quantifying the volume of available global groundwater, studies which aim to assess its magnitude are limited in number. They are further restricted in scope and depth of analysis as, in most cases, they do not explain how the estimates of global groundwater resources have been obtained, what methods have been used to generate the figures and what levels of uncertainty exist. This article reviews the estimates of global groundwater resources. It finds that the level of uncertainty attached to existing numbers often exceeds 100 % and strives to establish the reasons for discrepancy. The outcome of this study outlines the need for a new agenda in water research with a more pronounced focus on groundwater. This new research agenda should aim at enhancing the quality and quantity of data provision on local and regional groundwater stocks and flows. This knowledge enhancement can serve as a basis to improve policy-making on groundwater resources globally. Research-informed policies will facilitate more effective groundwater management practices to ensure a more rapid progress of the global water sector towards the goal of sustainability

Deficiency of Huntingtin Has Pleiotropic Effects in the Social Amoeba Dictyostelium discoideum

Huntingtin is a large HEAT repeat protein first identified in humans, where a polyglutamine tract expansion near the amino terminus causes a gain-of-function mechanism that leads to selective neuronal loss in Huntington's disease (HD). Genetic evidence in humans and knock-in mouse models suggests that this gain-of-function involves an increase or deregulation of some aspect of huntingtin's normal function(s), which remains poorly understood. As huntingtin shows evolutionary conservation, a powerful approach to discovering its normal biochemical role(s) is to study the effects caused by its deficiency in a model organism with a short life-cycle that comprises both cellular and multicellular developmental stages. To facilitate studies aimed at detailed knowledge of huntingtin's normal function(s), we generated a null mutant of hd, the HD ortholog in Dictyostelium discoideum. Dictyostelium cells lacking endogenous huntingtin were viable but during development did not exhibit the typical polarized morphology of Dictyostelium cells, streamed poorly to form aggregates by accretion rather than chemotaxis, showed disorganized F-actin staining, exhibited extreme sensitivity to hypoosmotic stress, and failed to form EDTA-resistant cell–cell contacts. Surprisingly, chemotactic streaming could be rescued in the presence of the bivalent cations Ca2+ or Mg2+ but not pulses of cAMP. Although hd− cells completed development, it was delayed and proceeded asynchronously, producing small fruiting bodies with round, defective spores that germinated spontaneously within a glassy sorus. When developed as chimeras with wild-type cells, hd− cells failed to populate the pre-spore region of the slug. In Dictyostelium, huntingtin deficiency is compatible with survival of the organism but renders cells sensitive to low osmolarity, which produces pleiotropic cell autonomous defects that affect cAMP signaling and as a consequence development. Thus, Dictyostelium provides a novel haploid organism model for genetic, cell biological, and biochemical studies to delineate the functions of the HD protein

Regulation of the Escherichia coli HipBA Toxin-Antitoxin System by Proteolysis

Bacterial populations produce antibiotic-tolerant persister cells. A number of recent studies point to the involvement of toxin/antitoxin (TA) modules in persister formation. hipBA is a type II TA module that codes for the HipB antitoxin and the HipA toxin. HipA is an EF-Tu kinase, which causes protein synthesis inhibition and dormancy upon phosphorylation of its substrate. Antitoxins are labile proteins that are degraded by one of the cytosolic ATP-dependent proteases. We followed the rate of HipB degradation in different protease deficient strains and found that HipB was stabilized in a lon- background. These findings were confirmed in an in vitro degradation assay, showing that Lon is the main protease responsible for HipB proteolysis. Moreover, we demonstrated that degradation of HipB is dependent on the presence of an unstructured carboxy-terminal stretch of HipB that encompasses the last 16 amino acid residues. Further, substitution of the conserved carboxy-terminal tryptophan of HipB to alanine or even the complete removal of this 16 residue fragment did not alter the affinity of HipB for hipBA operator DNA or for HipA indicating that the major role of this region of HipB is to control HipB degradation and hence HipA-mediated persistence