A randomized trial of alendronate as prophylaxis against loss in bone mineral density following lymphoma treatment

Lymphoma patients often receive high glucocorticoid doses as part of standard therapy. Observational studies have shown a substantial risk of glucocorticoid-induced osteoporosis (GIO) with associated fractures. The aim of the SIESTA trial was to determine if oral alendronate (ALN) is a safe and effective prophylaxis against GIO in lymphoma. SIESTA was a single-center, randomized, double-blinded, phase 2 study of lymphoma patients planned for glucocorticoid-containing chemotherapy. After randomization, patients received weekly ALN 70 mg or placebo for a total of 52 weeks. Bone mineral density (BMD) was assessed at baseline, after completion of chemotherapy (end of treatment [EOT]) (4 to 6 months), and at the end of the study (EOS) (12 months). Vertebral fracture and biomarkers were assessed at baseline and EOS. Patients with baseline BMD assessment and at least 1 follow-up BMD assessment were analyzed for efficacy. The primary endpoint was a change in lumbar spine T-score from baseline to EOS. Of the 59 patients enrolled, 23 of 30 in the ALN arm and 24 of 29 in the placebo arm were analyzed for efficacy. The mean change in T-score from baseline to 12 months at the lumbar spine was +0.15 for ALN and -0.12 for placebo (P = .023). The difference in ΔT(EOS) between the ALN and placebo groups was larger among females (ALN 0.28; placebo -0.28; P = .01). Biomarker analyses confirmed reduced bone resorption in ALN-treated patients. In conclusion, ALN is a safe and effective primary prophylaxis against loss in BMD following glucocorticoid-containing chemotherapy. Despite reduced BMD loss in the ALN arm, the treatment did not influence fracture risk in this small cohort of patients

Canopy nitrogen, carbon assimilation, and albedo in temperate and boreal forests: Functional relations and potential climate feedbacks

The availability of nitrogen represents a key constraint on carbon cycling in terrestrial ecosystems, and it is largely in this capacity that the role of N in the Earth\u27s climate system has been considered. Despite this, few studies have included continuous variation in plant N status as a driver of broad-scale carbon cycle analyses. This is partly because of uncertainties in how leaf-level physiological relationships scale to whole ecosystems and because methods for regional to continental detection of plant N concentrations have yet to be developed. Here, we show that ecosystem CO2 uptake capacity in temperate and boreal forests scales directly with whole-canopy N concentrations, mirroring a leaf-level trend that has been observed for woody plants worldwide. We further show that both CO2 uptake capacity and canopy N concentration are strongly and positively correlated with shortwave surface albedo. These results suggest that N plays an additional, and overlooked, role in the climate system via its influence on vegetation reflectivity and shortwave surface energy exchange. We also demonstrate that much of the spatial variation in canopy N can be detected by using broad-band satellite sensors, offering a means through which these findings can be applied toward improved application of coupled carbon cycle–climate models

The Occurrence of Photorhabdus-Like Toxin Complexes in Bacillus thuringiensis

Recently, genomic sequencing of a Bacillus thuringiensis (Bt) isolate from our collection revealed the presence of an apparent operon encoding an insecticidal toxin complex (Tca) similar to that first described from the entomopathogen Photorhabdus luminescens. To determine whether these genes are widespread among Bt strains, we screened isolates from the collection for the presence of tccC, one of the genes needed for the expression of fully functional toxin complexes. Among 81 isolates chosen to represent commonly encountered biochemical phenotypes, 17 were found to possess a tccC. Phylogenetic analysis of the 81 isolates by multilocus sequence typing revealed that all the isolates possessing a tccC gene were restricted to two sequence types related to Bt varieties morrisoni, tenebrionis, israelensis and toumanoffi. Sequencing of the ∼17 kb tca operon from two isolates representing each of the two sequence types revealed >99% sequence identity. Optical mapping of DNA from Bt isolates representing each of the sequence types revealed nearly identical plasmids of ca. 333 and 338 kbp, respectively. Selected isolates were found to be toxic to gypsy moth larvae, but were not as effective as a commercial strain of Bt kurstaki. Some isolates were found to inhibit growth of Colorado potato beetle. Custom Taqman® relative quantitative real-time PCR assays for Tc-encoding Bt revealed both tcaA and tcaB genes were expressed within infected gypsy moth larvae

Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria

Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism. Keywords: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPaseNational Institutes of Health (U.S.) (Grant F32 DK095726)National Institutes of Health (U.S.) (Grant R01 GM049224

Development of a Precision Medicine Workflow in Hematological Cancers, Aalborg University Hospital, Denmark

Within recent years, many precision cancer medicine initiatives have been developed. Most of these have focused on solid cancers, while the potential of precision medicine for patients with hematological malignancies, especially in the relapse situation, are less elucidated. Here, we present a demographic unbiased and observational prospective study at Aalborg University Hospital Denmark, referral site for 10% of the Danish population. We developed a hematological precision medicine workflow based on sequencing analysis of whole exome tumor DNA and RNA. All steps involved are outlined in detail, illustrating how the developed workflow can provide relevant molecular information to multidisciplinary teams. A group of 174 hematological patients with progressive disease or relapse was included in a non-interventional and population-based study, of which 92 patient samples were sequenced. Based on analysis of small nucleotide variants, copy number variants, and fusion transcripts, we found variants with potential and strong clinical relevance in 62% and 9.5% of the patients, respectively. The most frequently mutated genes in individual disease entities were in concordance with previous studies. We did not find tumor mutational burden or micro satellite instability to be informative in our hematologic patient cohort

Soil carbon fluxes and stocks in a Great Lakes forest chronosequence

Author Posting. © The Authors, 2008. This is the author's version of the work. It is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Global Change Biology 15 (2009): 145-155, doi:10.1111/j.1365-2486.2008.01741.x.We measured soil respiration and soil carbon stocks, as well as micrometeorological variables in a chronosequence of deciduous forests in Wisconsin and Michigan. The chronosequence consisted of (1) four recently disturbed stands, including a clearcut and repeatedly burned stand (burn), a blowdown and partial salvage stand (blowdown), a clearcut with sparse residual overstory (residual), and a regenerated stand from a complete clearcut (regenerated); (2) four young aspen (Populus tremuloides) stands in average age of 10 years; (3) four intermediate aspen stands in average age of 26 years; (4) four mature northern hardwood stands in average age of 73 years; and (5) an old-growth stand approximately 350 years old. We fitted site-based models and used continuous measurements of soil temperature to estimate cumulative soil respiration for the growing season of 2005 (days 133 to 295). Cumulative soil respiration in the growing season was estimated to be 513, 680, 747, 747, 794, 802, 690, and 571 gC m-2 in the burn, blowdown, residual, regenerated, young, intermediate, mature, and old-growth stands, respectively. The measured apparent temperature sensitivity of soil respiration was the highest in the regenerated stand, and declined from the young stands to the old-growth. Both cumulative soil respiration and basal soil respiration at 10˚C increased during stand establishment, peaked at intermediate age, and then decreased with age. Total soil carbon at 0-60 cm initially decreased after harvest, and increased after stands established. The old-growth stand accumulated carbon in deep layers of soils, but not in the surface soils. Our study suggests a complexity of long-term soil carbon dynamics, both in vertical depth and temporal scale.This work was primarily funded by the Office of Science/BER, U.S. Department of Energy Terrestrial Carbon Processes program (DE-FG02-00ER63023 and DE-FG02-03ER63682), and NASA Terrestrial Ecology Program (NNG05GD51G)

Feasibility of a multidimensional home-based exercise programme for the elderly with structured support given by the general practitioner's surgery: Study protocol of a single arm trial preparing an RCT [ISRCTN58562962]

<p>Abstract</p> <p>Background</p> <p>Physical activity programmes can help to prevent functional decline in the elderly. Until now, such programmes use to target either on healthy community-dwelling seniors or on elderly living in special residences or care institutions. Sedentary or frail people, however, are difficult to reach when they live in their own homes. The general practitioner's (GP) practice offers a unique opportunity to acquire these people for participation in activity programmes. We conceptualised a multidimensional home-based exercise programme that shall be delivered to the target group through cooperation between GPs and exercise therapists. In order to prepare a randomised controlled trial (RCT), a feasibility study is being conducted.</p> <p>Methods</p> <p>The study is designed as a single arm interventional trial. We plan to recruit 90 patients aged 70 years and above through their GPs. The intervention lasts 12 weeks and consists of physical activity counselling, a home-exercise programme, and exercise consultations provided by an exercise therapist in the GP's practice and via telephone. The exercise programme consists of two main components: 1. a combination of home-exercises to improve strength, flexibility and balance, 2. walking for exercise to improve aerobic capacity. Primary outcome measures are: appraisal by GP, undesirable events, drop-outs, adherence. Secondary outcome measures are: effects (a. motor tests: timed-up-and-go, chair rising, grip strength, tandem stand, tandem walk, sit-and-reach; b. telephone interview: PRISCUS-Physical Activity Questionnaire, Short Form-8 Health Survey, three month recall of frequency of falls, Falls Efficacy Scale), appraisal by participant, exercise performance, focus group discussion. Data analyses will focus on: 1. decision-making concerning the conduction of a RCT, 2. estimation of the effects of the programme, detection of shortcomings and identification of subgroups with contrary results, 3. feedback to participants and to GPs.</p> <p>Conclusion</p> <p>A new cooperation between GPs and exercise therapists to approach community-dwelling seniors and to deliver a home-exercise programme is object of research with regard to feasibility and acceptance. In case of success, an RCT should examine the effects of the programme. A future implementation within primary medical care may take advantage from the flexibility of the programme.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN58562962.</p