Planetary Protection Knowledge Gaps for Human Extraterrestrial Missions: Workshop Report

This report on Planetary Protection Knowledge Gaps for Human Extraterrestrial Missions summarizes the presentations, deliberations and findings of a workshop at NASA Ames Research Center, March 24-26, 2015, which was attended by more than 100 participants representing a diverse mix of science, engineering, technology, and policy areas. The main objective of the three-day workshop was to identify specific knowledge gaps that need to be addressed to make incremental progress towards the development of NASA Procedural Requirements (NPRs) for Planetary Protection during human missions to Mars

Planetary Protection Concerns During Pre-Launch Radioisotope Power System Final Integration Activities

The Advanced Stirling Radioisotope Generator (ASRG) is a next-generation radioisotope-based power system that is currently being developed as an alternative to the Multi-Mission Radioisotope Thermoelectric Generator (MMRTG). Power sources such as these may be needed for proposed missions to solar system planets and bodies that have challenging Planetary Protection (PP) requirements (e.g. Mars, Europa, Enceladus) that may support NASA s search for life, remnants of past life, and the precursors of life. One concern is that the heat from the ASRG could potentially create a region in which liquid water may occur. As advised by the NASA Planetary Protection Officer, when deploying an ASRG to Mars, the current COSPAR/NASA PP policy should be followed for Category IVc mission. Thus, sterilization processing of the ASRG to achieve bioburden reduction would be essential to meet the Planetary Protection requirements. Due to thermal constraints and associated low temperature limits of elements of the ASRG, vapor hydrogen peroxide (VHP) was suggested as a candidate alternative sterilization process to complement dry heat microbial reduction (DHMR) for the assembled ASRG. The following proposed sterilization plan for the ASRG anticipates a mission Category IVc level of cleanliness. This plan provides a scenario in which VHP is used as the final sterilization process. Keywords: Advanced Stirling Radioisotope Generator (ASRG), Planetary Protection (PP), Vapor hydrogen peroxide (VHP) sterilization

Experimental Modeling of Sterilization Effects for Atmospheric Entry Heating on Microorganisms

The objective of this research was to design, build, and test an experimental apparatus for studying the parameters of atmospheric entry heating, and the inactivation of temperature-resistant bacterial spores. The apparatus is capable of controlled, rapid heating of sample coupons to temperatures of 200 to 350 C and above. The vacuum chamber permits operation under vacuum or special atmospheric gas mixtures

Time on androgen deprivation therapy and adaptations to exercise: secondary analysis from a 12-month randomized controlled trial in men with prostate cancer

Objectives To explore if duration of previous exposure to androgen deprivation therapy (ADT) in men with prostate cancer (PCa) undertaking a year-long exercise programme moderates the exercise response with regard to body composition and muscle performance, and also to explore the moderator effects of baseline testosterone, time since ADT, and baseline value of the outcome. Patients and Methods In a multicentre randomized controlled trial, 100 men who had previously undergone either 6 months (short-term) or 18 months (long-term) of ADT in combination with radiotherapy, as part of the TROG 03.04 RADAR trial, were randomized to 6 months supervised exercise, followed by a 6-month home-based maintenance programme, or to printed physical activity educational material for 12 months across 13 university-affiliated exercise clinics in Australia and New Zealand. The participants were long-term survivors of PCa with a mean age of 71.7 ± 6.4 years, and were assessed for lower extremity performance (repeated chair rise), with a subset of men (n = 57) undergoing additional measures for upper and lower body muscle strength and body composition (lean mass, fat mass, appendicular skeletal muscle [ASM]) by dual X-ray absorptiometry. Data were analysed using generalized estimating equations. Results Time on ADT significantly moderated the exercise effects on chair rise (βinteraction = −1.3 s, 95% confidence interval [CI] −2.6 to 0.0), whole-body lean mass (βinteraction = 1194 g, 95% CI 234 to 2153) and ASM mass (βinteraction = 562 g, 95% CI 49 to 1075), and approached significance for fat mass (βinteraction = −1107 g, 95% CI −2346 to 132), with greater benefits for men previously on long-term ADT. At 6 months, the intervention effects on chair rise time −1.5 s (95% CI −2.5 to −0.5), whole-body lean mass 824 g (95% CI 8 to 1640), ASM mass 709 g (95% CI 260 to 1158), and fat mass −1377 g (95% CI −2156 to −598) were significant for men previously on long-term ADT, but not for men on short-term ADT. At 12 months, the intervention effects for men on long-term ADT remained significant for the chair rise, with improved performance (−2.0 s, 95% CI −3.0 to −1.0) and increased ASM (537 g, 95% CI 153 to 921). Time on ADT did not moderate the exercise effects on muscle strength, nor did time since ADT cessation moderate any intervention effects. Similarly, testosterone and baseline values of the outcome had negligible moderator effects. Conclusions Men with PCa previously treated long-term with ADT respond more favourably to exercise in terms of lower body muscle performance and body composition (lean and fat mass, and ASM) than those with short-term ADT exposure. As a result, men who were formerly on long-term androgen suppression regimens should be especially prescribed exercise medicine interventions to alleviate residual treatment-related adverse effects

Exercise Preserves Physical Function in Prostate Cancer Patients with Bone Metastases

The presence of bone metastases has excluded participation of cancer patients in exercise interventions and is a relative contraindication to supervised exercise in the community setting due to concerns of fragility fracture. We examined the efficacy and safety of a modular multi-modal exercise program in prostate cancer patients with bone metastases.Between 2012 and 2015, 57 prostate cancer patients (70.0±8.4 years; BMI 28.7±4.0 kg/m) with bone metastases (pelvis 75.4%, femur 40.4%, rib/thoracic spine 66.7%, lumbar spine 43.9%, humerus 24.6%, other sites 70.2%) were randomised to multi-modal supervised aerobic, resistance and flexibility exercises undertaken thrice weekly (EX, n=28) or usual care (CON, n=29) for 3 months. Physical function subscale of the SF-36 was the primary endpoint as an indicator of patient-rated physical functioning. Secondary endpoints included objective measures of physical function, lower body muscle strength, body composition and fatigue. Safety was assessed by recording the incidence and severity of any adverse events, skeletal complications, and bone pain throughout the intervention.There was a significant difference between groups for self-reported physical functioning (3.2 points, 95% CI 0.4-6.0 points; p=0.028) and lower body muscle strength (6.6 kg, 95% CI 0.6-12.7; p =0.033) at 3 months favouring EX. However, there was no difference between groups for lean mass (p=0.584), fat mass (p=0.598), or fatigue (p=0.964). There were no exercise-related adverse events or skeletal fractures and no differences in bone pain between EX and CON (p=0.507).Multi-modal modular exercise in prostate cancer patients with bone metastases led to self-reported improvements in physical function and objectively measured lower body muscle strength with no skeletal complications or increased bone pain.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments

Malaria parasites (Plasmodium spp.) encounter markedly different (nutritional) environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA) metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission-blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Seeking Signs of Life on Mars: A Strategy for Selecting and Analyzing Returned Samples from Hydrothermal Deposits

Highly promising locales for biosignature prospecting on Mars are ancient hydrothermal deposits, formed by the interaction of surface water with heat from volcanism or impacts. On Earth, they occur throughout the geological record (to at least approx. 3.5 Ga), preserving robust mineralogical, textural and compositional evidence of thermophilic microbial activity. Hydrothermal systems were likely present early in Mars' history, including at two of the three finalist candidate landing sites for M2020, Columbia Hills and NE Syrtis Major. Hydrothermal environments on Earth's surface are varied, constituting subaerial hot spring aprons, mounds and fumaroles; shallow to deep-sea hydrothermal vents (black and white smokers); and vent mounds and hot-spring discharges in lacustrine and fluvial settings. Biological information can be preserved by rapid, spring-sourced mineral precipitation, but also could be altered or destroyed by postdepositional events. Thus, field observations need to be followed by detailed laboratory analysis to verify potential biosignatures. See Attachmen