Efficacy of Anamorelin, a novel non-peptide ghrelin analogue, in patients with advanced non-small cell lung cancer (NSCLC) and Cachexia—Review and expert opinion

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Cancer cachexia is a multilayered syndrome consisting of the interaction between tumor cells and the host, at times modulated by the pharmacologic treatments used for tumor control. Key cellular and soluble mediators, activated because of this interaction, induce metabolic and nutritional alterations. This results in mass and functional changes systemically, and can lead to increased morbidity and reduced length and quality of life. For most solid malignancies, a cure remains an unrealistic goal, and targeting the key mediators is ineffective because of their heterogeneity/redundancy. The most beneficial approach is to target underlying systemic mechanisms, an approach where the novel non-peptide ghrelin analogue anamorelin has the advantage of stimulating appetite and possibly food intake, as well as promoting anabolism and significant muscle mass gain. In the ROMANA studies, compared with placebo, anamorelin significantly increased lean body mass in non-small cell lung cancer (NSCLC) patients. Body composition analysis suggested that anamorelin is an active anabolic agent in patients with NSCLC, without the side effects of other anabolic drugs. Anamorelin also induced a significant and meaningful improvement of anorexia/cachexia symptoms. The ROMANA trials have provided unprecedented knowledge, highlighting the therapeutic effects of anamorelin as an initial, but significant, step toward directly managing cancer cachexia

Conformational analysis of nucleic acids revisited: Curves+

We describe Curves+, a new nucleic acid conformational analysis program which is applicable to a wide range of nucleic acid structures, including those with up to four strands and with either canonical or modified bases and backbones. The program is algorithmically simpler and computationally much faster than the earlier Curves approach, although it still provides both helical and backbone parameters, including a curvilinear axis and parameters relating the position of the bases to this axis. It additionally provides a full analysis of groove widths and depths. Curves+ can also be used to analyse molecular dynamics trajectories. With the help of the accompanying program Canal, it is possible to produce a variety of graphical output including parameter variations along a given structure and time series or histograms of parameter variations during dynamic

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

What Happens to bone health during and after spaceflight?

Weightless conditions of space flight accelerate bone loss. There are no reports to date that address whether the bone that is lost during spaceflight could ever be recovered. Spaceinduced bone loss in astronauts is evaluated at the Johnson Space Center (JSC) by measurement of bone mineral density (BMD) by Dual-energy x-ray absorptiometry (DXA) scans. Astronauts are routinely scanned preflight and at various time points postflight (greater than or equal to Return+2 days). Two sets of BMD data were used to model spaceflight-induced loss and skeletal recovery in crewmembers following long-duration spaceflight missions (4-6 months). Group I was from astronauts (n=7) who were systematically scanned at multiple time points during the postflight period as part of a research protocol to investigate skeletal recovery. Group II came from a total of 49 sets of preflight and postflight data obtained by different protocols. These data were from 39 different crewmembers some of whom served on multiple flights. Changes in BMD (between pre- and postflight BMD) were plotted as a function of time (days-after-landing); plotted data were fitted to an exponential equation which enabled estimations of i) BMD change at day 0 after landing and ii) the number of days by which 50% of the lost bone is recovered (half-life). These fits were performed for BMD of the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. There was consistency between the models for BMD recovery. Based upon the exponential model of BMD restoration, recovery following long-duration missions appears to be substantially complete in crewmembers within 36 months following return to Earth

The effects of a video intervention on posthospitalization pulmonary rehabilitation uptake

Rationale: Pulmonary rehabilitation (PR) after hospitalizations for exacerbations of chronic obstructive pulmonary disease (COPD) improves exercise capacity and health-related quality of life and reduces readmissions. However, posthospitalization PR uptake is low. To date, no trials of interventions to increase uptake have been conducted.Objectives: To study the effect of a codesigned education video as an adjunct to usual care on posthospitalization PR uptake.Methods: The present study was an assessor- and statistician-blinded randomized controlled trial with nested, qualitative interviews of participants in the intervention group. Participants hospitalized with COPD exacerbations were assigned 1:1 to receive either usual care (COPD discharge bundle including PR information leaflet) or usual care plus the codesigned education video delivered via a handheld tablet device at discharge. Randomization used minimization to balance age, sex, FEV1 % predicted, frailty, transport availability, and previous PR experience.Measurements and Main Results: The primary outcome was PR uptake within 28 days of hospital discharge. A total of 200 patients were recruited, and 196 were randomized (51% female, median FEV1% predicted, 36 [interquartile range, 27-48]). PR uptake was 41% and 34% in the usual care and intervention groups, respectively (P = 0.37), with no differences in secondary (PR referral and completion) or safety (readmissions and death) endpoints. A total of 6 of the 15 participants interviewed could not recall receiving the video.Conclusions: A codesigned education video delivered at hospital discharge did not improve posthospitalization PR uptake, referral, or completion

An assessment of the strength of knots and splices used as eye terminations in a sailing environment

Research into knots, splices and other methods of forming an eye termination has been limited, despite the fact that they are essential and strongly affect the performance of a rope. The aim of this study was to carry out a comprehensive initial assessment of the breaking strength of eye terminations commonly used in a sailing environment, thereby providing direction for further work in the field. Supports for use in a regular tensile testing machine were specially developed to allow individual testing of each sample and a realistic spread of statistical data to be obtained. Over 180 break tests were carried out on four knots (the bowline, double bowline, figure-of-eight loop and perfection loop) and two splices (three-strand eye splice and braid-on-braid splice). The factors affecting their strength were investigated. A statistical approach to the analysis of the results was adopted. The type of knot was found to have a significant effect on the strength. This same effect was seen in both types of rope construction (three-strand and braid-on-braid). Conclusions were also drawn as to the effect of splice length, eye size, manufacturer and rope diameter on the breaking strength of splices. Areas of development and further investigation were identified

Plasmon Lifetime in K: A Case Study of Correlated Electrons in Solids Amenable to Ab Initio Theory

On the basis of a new ab initio, all-electron response scheme, formulated within time-dependent density-functional theory, we solve the puzzle posed by the anomalous dispersion of the plasmon linewidth in K. The key damping mechanism is shown to be decay into particle-hole pairs involving empty states of d-symmetry. While the effect of many-particle correlations is small, the correlations built into the "final-state" -d-bands play an important, and novel, role ---which is related to the phase-space complexity associated with these flat bands. Our case study of plasmon lifetime in K illustrates the importance of ab initio paradigms for the study of excitations in correlated-electron systems.Comment: 12 pages, 4 figures, for html browsing see http://web.utk.edu/~weik

Development of non-antibiotic-resistant, chromosomally based, constitutive and inducible expression systems for aroA-attenuated Salmonella enterica serovar typhimurium

Live-vaccine delivery systems expressing two model antigens from Mycoplasma hyopneumoniae, F2(P97) (Adh) and NrdF, were constructed using Salmonella enterica serovar Typhimurium aroA (STM-1), and immunogenicity in mice was evaluated. Recombinant plasmid-based expression (PBE) and chromosomally based expression (CBE) systems were constructed. The PBE system was formed by cloning both antigen genes into pJLA507 to create an operon downstream of temperature-inducible promoters. Constitutive CBE was achieved using a promoter-trapping technique whereby the promoterless operon was stably integrated into the chromosome of STM-1, and the expression of antigens was assessed. The chromosomal position of the operon was mapped in four clones. Inducible CBE was obtained by using the in vivo-induced sspA promoter and recombining the expression construct into aroD. Dual expression of the antigens was detected in all systems, with PBE producing much larger quantities of both antigens. The stability of antigen expression after in vivo passage was 100% for all CBE strains recovered. PBE and CBE strains were selected for comparison in a vaccination trial. The vaccine strains were delivered orally into mice, and significant systemic immunoglobulin M(IgM) and IgG responses against both antigens were detected among all CBE groups. No significant immune response was detected using PBE strains. Expression of recombinant antigens in S. enterica serovar Typhimurium aroA from chromosomally located strong promoters without the use of antibiotic resistance markers is a reliable and effective method of inducing a significant immune response