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All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Microbial vitamin biosynthesis links gut microbiota dynamics to chemotherapy toxicity

ABSTRACT Dose-limiting toxicities pose a major barrier to cancer treatment. While preclinical studies show that the gut microbiota influences and is influenced by anticancer drugs, data from patients paired with careful side effect monitoring remains limited. Here, we investigate capecitabine (CAP)-microbiome interactions through longitudinal metagenomic sequencing of stool from 56 advanced colorectal cancer patients. CAP significantly altered the gut microbiome, enriching for menaquinol (vitamin K2) biosynthesis genes. Transposon library screens, targeted gene deletions, and media supplementation revealed that menaquinol biosynthesis protectsEscherichia colifrom drug toxicity. Stool menaquinol gene and metabolite levels were associated with decreased peripheral sensory neuropathy. Machine learning models trained in this cohort predicted toxicities in an independent cohort. Taken together, these results suggest treatment-associated increases in microbial vitamin biosynthesis serve a chemoprotective role for bacterial and host cells. Further, our findings provide a foundation for in-depth mechanistic dissection, human intervention studies, and extension to other cancer treatments. IMPORTANCE Side effects are common during the treatment of cancer. The trillions of microbes found within the human gut are sensitive to anticancer drugs, but the effects of treatment-induced shifts in gut microbes for side effects remain poorly understood. We profiled gut microbes in colorectal cancer patients treated with capecitabine and carefully monitored side effects. We observed a marked expansion in genes for producing vitamin K2 (menaquinone). Vitamin K2 rescued gut bacterial growth and was associated with decreased side effects in patients. We then used information about gut microbes to develop a predictive model of drug toxicity that was validated in an independent cohort. These results suggest that treatment-associated increases in bacterial vitamin production protect both bacteria and host cells from drug toxicity, providing new opportunities for intervention and motivating the need to better understand how dietary intake and bacterial production of micronutrients like vitamin K2 influence cancer treatment outcomes.

Microbiology↗
NASA NTRS1993

Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine

PURPOSE: To investigate the efficacy and safety of midodrine for treatment of patients with orthostatic hypotension due to autonomic failure. PATIENTS: Ninety-seven patients with orthostatic hypotension were randomized in a 4-week, double-blinded, placebo-controlled study with a 1-week placebo run-in period. Patients ranged in age from 22 to 86 years (mean: 61 years). METHODS: After a 1-week run-in phase, either placebo or midodrine at a dose of 2.5 mg, 5 mg, or 10 mg was administered three times a day for 4 weeks. Both the placebo group and the 2.5-mg midodrine group received constant doses throughout the double-blind phase. The patients receiving 5 mg or 10 mg of midodrine were given doses that were increased at weekly intervals by 2.5-mg increments until the designated dose was reached. Efficacy evaluations were based on an improvement at 1-hour postdose in standing systolic blood pressure and in symptoms of orthostatic hypotension (syncope, dizziness/lightheadedness, weakness/fatigue, and low energy level). RESULTS: Midodrine (10 mg) increased standing systolic blood pressure by 22 mm Hg (28%, p < 0.001 versus placebo). Midodrine improved (p < 0.05) the following symptoms of orthostatic hypotension compared to placebo: dizziness/lightheadedness, weakness/fatigue, syncope, low energy level, impaired ability to stand, and feelings of depression. The overall side effects were mainly mild to moderate. One or more side effects were reported by 22% of the placebo group compared with 27% of the midodrine-treated group. Scalp pruritus/tingling, which was reported by 10 of 74 (13.5%) of the midodrine-treated patients, was most frequent. Other reported side effects included supine hypertension (8%) and feelings of urinary urgency (4%). CONCLUSION: We conclude that midodrine is an effective and well-tolerated treatment for moderate-to-severe orthostatic hypotension associated with autonomic failure.

NASA Discipline Number 14-10↗
DOE OSTI2023

Multimodal representation learning for predicting molecule–disease relations

Motivation: Predicting molecule–disease indications and side effects is important for drug development and pharmacovigilance. Comprehensively mining molecule–molecule, molecule–disease and disease–disease semantic dependencies can potentially improve prediction performance. Methods: We introduce a Multi-Modal REpresentation Mapping Approach to Predicting molecular-disease relations (M2REMAP) by incorporating clinical semantics learned from electronic health records (EHR) of 12.6 million patients. Specifically, M2REMAP first learns a multimodal molecule representation that synthesizes chemical property and clinical semantic information by mapping molecule chemicals via a deep neural network onto the clinical semantic embedding space shared by drugs, diseases and other common clinical concepts. To infer molecule–disease relations, M2REMAP combines multimodal molecule representation and disease semantic embedding to jointly infer indications and side effects. Results: We extensively evaluate M2REMAP on molecule indications, side effects and interactions. Results show that incorporating EHR embeddings improves performance significantly, for example, attaining an improvement over the baseline models by 23.6% in PRC-AUC on indications and 23.9% on side effects. Further, M2REMAP overcomes the limitation of existing methods and effectively predicts drugs for novel diseases and emerging pathogens. Availability and implementation: The code is available at https://github.com/celehs/M2REMAP, and prediction results are provided at https://shiny.parse-health.org/drugs-diseases-dev/.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1984

The Safety of Contrast Echocardiography: Report of the Committee on Contrast Echocardiography for the American Society of Echocardiography

The results of a survey of 363 physicians performing were evaluated to assess the relative safety of contrast echocardiography. Fifteen physicians reported a variety of transient side effects, including neurologic and respiratory symptoms. Although contrast echocardiography appeared to carry some risk for side effects, that risk was low (0.062%) and no residual side effects or complications were observed.

Bommer, W. J.↗
NASA NTRS2011

Pharmacokinetics of Scopolamine Intranasal Gel Formulation (INSCOP) During Antiorthostatic Bedrest

Space Motion sickness (SMS) is an age old problem for space travelers on short and long duration space flight Oral antiemetics are not very effective in space due to poor bioavailability. Scopolamine (SCOP) is the most frequently used drug by recreational travelers V patch, tablets available on the market. Common side effects of antiemetics, in general, include drowsiness, sedation, dry mouth and reduced psychomotor performance. Severity and persistence of side effects are often dose related Side effects can be detrimental in high performance demanding settings, e.g. space flight, military.

Putcha, Lakshmi↗
NASA NTRS2003

Temazepam, but not zolpidem, causes orthostatic hypotension in astronauts after spaceflight

Insomnia is a common symptom, not only in the adult population but also in many astronauts. Hypnotics, such as temazepam (a benzodiazepine) and zolpidem (an imidazopyridine), are often taken to relieve insomnia. Temazepam has been shown clinically to have hemodynamic side effects, particularly in the elderly; however, the mechanism is not clear. Zolpidem does not cause hemodynamic side effects. The purpose of this study was to determine whether the use of different hypnotics during spaceflight might contribute significantly to the high incidence of postflight orthostatic hypotension, and to compare the findings in astronauts with clinical research. Astronauts were separated into three groups: control (n = 40), temazepam (15 or 30 mg; n = 9), and zolpidem (5 or 10 mg; n = 8). In this study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand tests before spaceflight and on landing day. On landing day, systolic pressure decreased significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight when astronauts are hemodynamically compromised. Temazepam should not be the initial choice as a sleeping aid for astronauts. These results in astronauts may help to explain the hemodynamic side effects in the elderly who are also compromised. Zolpidem may be a better choice as a sleeping aid in these populations.

STS Shuttle Project↗
NASA NTRS2005

Nutrition for Space Exploration

Nutrition has proven to be critical throughout the history of human exploration, on both land and water. The importance of nutrition during long-duration space exploration is no different. Maintaining optimal nutritional status is critical for all bodily systems, especially in light of the fact that that many are also affected by space flight itself. Major systems of concern are bone, muscle, the cardiovascular system, the immune system, protection against radiation damage, and others. The task ahead includes defining the nutritional requirements for space travelers, ensuring adequacy of the food system, and assessing crew nutritional status before, during, and after flight. Accomplishing these tasks will provide significant contributions to ensuring crew health on long-duration missions. In addition, development and testing of nutritional countermeasures to effects of space flight is required, and assessment of the impact of other countermeasures (such as exercise and pharmaceuticals) on nutrition is also critical for maintaining overall crew health. Vitamin D stores of crew members are routinely low after long-duration space flight. This occurs even when crew members take vitamin D supplements, suggesting that vitamin D metabolism may be altered during space flight. Vitamin D is essential for efficient absorption of calcium, and has numerous other benefits for other tissues with vitamin D receptors. Protein is a macronutrient that requires additional study to define the optimal intake for space travelers. Administration of protein to bed rest subjects can effectively mitigate muscle loss associated with disuse, but too much or too little protein can also have negative effects on bone. In another bed rest study, we found that the ratio of protein to potassium was correlated with the level of bone resorption: the higher the ratio, the more bone resorption. These relationships warrant further study to optimize the beneficial effect of protein on both bone and muscle during space flight. Omega3 fatty acids are currently being studied as a means of protecting against radiation-induced cancer. They have also recently been implicated as having a role in mitigating the physical wasting, or cachexia, caused by cancer. The mechanism of muscle loss associated with this type of cachexia is similar to the mechanism of muscle loss during disuse or space flight. Omega3 fatty acids have already been shown to have protective effects on bone and cardiovascular function. Omega3 fatty acids could be an ideal countermeasure for space flight because they have protective effects on multiple systems. A definition of optimal nutrient intake requirements for long-duration space travel should also include antioxidants. Astronauts are exposed to numerous sources of oxidative stress, including radiation, elevated oxygen exposure during extravehicular activity, and physical and psychological stress. Elevated levels of oxidative damage are related to increased risk for cataracts, cardiovascular disease, and cancer. Many groundbased studies show the protective effects of antioxidants against oxidative damage induced by radiation or oxygen. Balancing the diet with foods that have high levels of antioxidants would be another ideal countermeasure because it should have minimal side effects on crew health. Antioxidant supplements, however, are often used without having data on their effectiveness or side effects. High doses of supplements have been associated with bone and cardiovascular problems, but research on antioxidant effects during space flight has not been conducted. Much work must be done before we can send crews on exploration missions. Nutrition is often assumed to be the simple provision of food items that will be stable throughout the mission. As outlined briefly above, the situation is much more complex than food provision. As explorers throughout history have found, failure to truly understand the role of nutrition can be catastrophic. When huns are in environments unlike any they have seen before, this is more true than ever.

Smith, Scott M.↗
NASA NTRS1999

Ambient Light Intensity, Actigraphy, Sleep and Respiration, Circadian Temperature and Melatonin Rhythms and Daytime Performance of Crew Members During Space Flight on STS-90 and STS-95 Missions

Sleep disruption and associated waking sleepiness and fatigue are common during space flight. A survey of 58 crew members from nine space shuttle missions revealed that most suffered from sleep disruption, and reportedly slept an average of only 6.1 hours per day of flight as compared to an average of 7.9 hours per day on the ground. Nineteen percent of crewmembers on single shift missions and 50 percent of the crewmembers in dual shift operations reported sleeping pill usage (benzodiazepines) during their missions. Benzodiazepines are effective as hypnotics, however, not without adverse side effects including carryover sedation and performance impairment, anterograde amnesia, and alterations in sleep EEG. Our preliminary ground-based data suggest that pre-sleep administration of 0.3 mg of the pineal hormone melatonin may have the acute hypnotic properties needed for treating the sleep disruption of space flight without producing the adverse side effects associated with benzodiazepines. We hypothesize that pre-sleep administration of melatonin will result in decreased sleep latency, reduced nocturnal sleep disruption, improved sleep efficiency, and enhanced next-day alertness and cognitive performance both in ground-based simulations and during the space shuttle missions. Specifically, we have carried out experiments in which: (1) ambient light intensity aboard the space shuttle is assessed during flight; (2) the impact of space flight on sleep (assessed polysomnographically and actigraphically), respiration during sleep, circadian temperature and melatonin rhythms, waking neurobehavioral alertness and performance is assessed in crew members of the Neurolab and STS-95 missions; (3) the effectiveness of melatonin as a hypnotic is assessed independently of its effects on the phase of the endogenous circadian pacemaker in ground-based studies, using a powerful experimental model of the dyssomnia of space flight; (4) the effectiveness of melatonin as a hypnotic is assessed during the STS-90 (Neurolab) and STS-95 missions in a double-blind placebo-controlled trial. In both flight-based experiments, the effects of melatonin on sleep stages and spectral composition of the EEG during sleep will be determined as well as its effects on daytime alertness and performance; (5) the impact of space flight on sleep and waking neurobehavioral alertness and performance in 30-45-year-old astronauts is compared with its impact in a 77-year-old astronaut. This case study is the first to assess the effects of space flight on an older individual. Because the investigators are still blind to the treatment in this double-blind, placebo-controlled trial, preliminary results will be presented independent of the drug condition.

Czeisler, Charles A.↗
NASA NTRS2006

A Countermeasure for Space Motion Sickness

Overall, the results obtained in both the U.S. and the Russian space programs indicate that most space crews will experience some symptoms of motion sickness (MS) causing significant impact on the operational objectives that must be accomplished to assure mission success. At this time the primary countermeasure for MS requires the administration of Promethazine. Promethazine is not a benign drug, and is most frequently administered just prior to the sleep cycle to prevent its side effects from further compromising mission objectives. Clearly other countermeasures for SMS must be developed. Currently the primary focus is on two different technologies: (1) developing new and different pharmacological compounds with less significant side effects, (2) preflight training. The primary problem with all of these methods for controlling MS is time. New drugs that may be beneficial are years from testing and development, and preflight training requires a significant investment of crew time during an already intensive pre-launch schedule. Granted, motion sickness symptoms can be minimized with either of the two methods detailed above, however, it may be possible to develop a countermeasure that does not require either extensive adaptation time or exposure to motion sickness. Approximately 25 years ago Professor Geoffrey Melvill Jones presented his work on adaptation of the vestibuloocular reflex (VOR) using optically reversed vision (left-right prisms) during head rotations in the horizontal plane. It was of no surprise that most subjects experienced motion sickness while wearing the optically reversing prisms. However, a serendipitous finding emerged during this research showing that the same subjects did not experience motion sickness symptoms when wearing the reversing prisms under stroboscopic illumination. The mechanism, by which this side-effect was believed to have occurred, is not clearly understood. However, the fact that no motion sickness was ever noted, suggests the possibility of producing functionally useful adaptation during space flight without the penalty of disabling motion sickness by controlling the rate of the adaptive process by means of an appropriate stroboscopically presented environment. After several recent meetings with Professor Melvill Jones, we were encouraged to repeat the motion sickness portions of his and Mandl's 1981 stroboscopic experiment. In conducting this experiment we used a randomized cross-over design where subjects were randomly assigned to either a stroboscopic flash or no strobe for their first exposure in the experimental design. Twenty subjects (19 subjects completed the study) read a short passage from Treasure Island mounted on the wall approximately 1 m from their eyes while wearing left-right reversing prisms. The strobe on time of 3 microseconds and flash frequency of 4 Hz was set to equal that used in the original study. Motion sickness was scored using a modified Miller and Graybiel scale that we constructed to include symptoms that may be elicited under conditions where reversing prisms are worn. On this scale a score of 5 represented Malaise IIa (mild motion sickness) and a score of 8 or above is approaching frank sickness. Symptoms were tracked and recorded every 5 min during the task. Testing was limited to 30 min unless the subject had reached the MIIa score, at which time the test was terminated. Performance under stroboscopic illumination was significantly better than when the subjects read under normal room illumination while wearing the left-right reversing prisms. Based on these results we developed a goggle system using LCD material that can be strobed. To evaluate the effectiveness of stroboscopic goggles we tested an additional 9 subjects in addition to retesting 10 used in the stroboscopic pilot study described above. These 19 subjects wore a pair of strobing LCD goggles that could be cycled at 4 Hz. These subjects wore the goggles while also wearing left-right reversg prisms. Results while wearing the goggles showed that none of the 19 subjects scored at the MIIa level on the motion sickness rating scale. When the goggles did not flash (no strobe), 11 of the 19 developed symptoms above the MIIa criteria. As a countermeasure the goggles seem to be effective, even with an on time of 10 msec (time the goggles are clear). We have also collected anecdotal data, from our personnel in the Neuroscience Laboratory at the Johnson Space Center, suggesting that the goggles may effective in preventing carsickness.

Reschke, M. F.↗
NASA NTRS1993

Promethazine and its use as a treatment for space motion sickness

Until Mar. 1989, no effective treatment--either prophylactic or symptomatic--for space motion sickness (SMS) had been discovered. Since Mar. 1989, intramuscular (IM) promethazine (PMZ) has been used in the treatment of SMS with extremely favorably results reported by the crew. A retrospective study was undertaken to quantify the efficacy of IM PMZ since its institution and the incidence of its major anticipated side-effect drowsiness and sedation. The results from a standardized crew medical debriefing conducted immediately after landing and follow-up interviews with the crews were used in establishing the efficacy and incidence of side effects from treatment. Only crews from the first 44 Shuttle flights on their first mission were considered. For a total of 132 crewmembers, 96 exhibited symptoms of SMS; and, of these, 20 were treated with IM PMZ. Ninety percent of those receiving IM PMZ 25-50mg received nearly immediate (less than 2 hours) relief of symptoms and 75 percent required no further treatment through the first 2 days of spaceflight. Those not receiving this treatment did not have any near-term resolution of their symptoms, and 50 percent were still ill through the second day of flight. This represents a significant difference at the p = 0.46 level. In stark contrast to the 60 percent to 73 percent incidence of sedation or drowsiness reported in individuals treated with PMZ in terrestrial environment at the doses used here, less than 5 percent reported these symptoms during spaceflight. IM PMZ is an effective therapy for SMS and is associated with minimal incidence of sedation or drowsiness. This combination of efficacy that is absent of significant side effects represents a substantial improvement in the operational situation of crewmembers afflicted with SMS. Studies to understand the mechanisms underlying these observations will be undertaken in the future.

Bagian, James P.↗
NASA NTRSDate not supplied

Modified Autogenic Feedback Training Produces Effect on Motion Sickness

Motion sickness is a common physiological reaction to provocative motion and is characterized by a constellation of symptoms, including stomach awareness, nausea, emesis, pallor, sweating, hypersalivation, and fatigue. The emergence of these symptoms can pose a significant threat to safety, particularly in the context of aviation. Given its prevalence among aviators and its detrimental impact on performance, researchers have endeavored to identify effective countermeasures for motion sickness. Currently, many of the existing interventions are pharmacological in nature and while effective, they present a problem due to their associated adverse side effects. A modified two-hour version of Autogenic Feedback Training Exercise (AFTE) could be an effective countermeasure to motion sickness without adverse side effects. AFTE combines principles of autogenic therapy, biofeedback, and learning to teach individuals to control their own internal physiological reactions through a series of relaxation and arousal exercises. AFTE was administered over six days. On the first day, participants were exposed to provocative motion via a rotating chair test to collect baseline physiological data. AFTE sessions were conducted on four consecutive days and lasted approximately 30 minutes each session. Participants were exposed to the rotating chair again on the 6th day. Results: Participants (n = 16) were evaluated on the number of rotations experienced and cumulative minutes spun in the chair. Participants tended to ride longer (M = 21.0 min, SD = 16.56) and tolerated more rotations (M = 244.8 rotations, SD = 310.62) on their second rotating chair test compared to baseline (M = 14.0 min, SD = 9.35; M = 125.8 rotations, SD = 124.08; t(15) = 2.21, p = .02). A moderate effect size was recorded (Hedges’s g = 0.44). A modified two-hour version of the AFTE is effective at increasing tolerance of symptoms associated with motion sickness.

motion sickness↗
NASA NTRS1999

Avoiding Braess' Paradox Through Collective Intelligence

In an Ideal Shortest Path Algorithm (ISPA), at each moment each router in a network sends all of its traffic down the path that will incur the lowest cost to that traffic. In the limit of an infinitesimally small amount of traffic for a particular router, its routing that traffic via an ISPA is optimal, as far as cost incurred by that traffic is concerned. We demonstrate though that in many cases, due to the side-effects of one router's actions on another routers performance, having routers use ISPA's is suboptimal as far as global aggregate cost is concerned, even when only used to route infinitesimally small amounts of traffic. As a particular example of this we present an instance of Braess' paradox for ISPA'S, in which adding new links to a network decreases overall throughput. We also demonstrate that load-balancing, in which the routing decisions are made to optimize the global cost incurred by all traffic currently being routed, is suboptimal as far as global cost averaged across time is concerned. This is also due to "side-effects", in this case of current routing decision on future traffic. The theory of COllective INtelligence (COIN) is concerned precisely with the issue of avoiding such deleterious side-effects. We present key concepts from that theory and use them to derive an idealized algorithm whose performance is better than that of the ISPA, even in the infinitesimal limit. We present experiments verifying this, and also showing that a machine-learning-based version of this COIN algorithm in which costs are only imprecisely estimated (a version potentially applicable in the real world) also outperforms the ISPA, despite having access to less information than does the ISPA. In particular, this COIN algorithm avoids Braess' paradox.

Wolpert , David H.↗
DOE OSTI2021

Behavioral Determinants of Canadian Radiation Oncologists’ Use of Single Fraction Palliative Radiation Therapy for Uncomplicated Bone Metastases

A mainstay therapy for pain relief from uncomplicated bone metastases is external beam radiation therapy. Single fraction radiation therapy (SFRT) is more convenient and cost-effective, causes fewer acute side effects, and is equivalent to multiple fraction radiation therapy for pain relief. Despite these advantages, radiation oncologists seldom prescribe SFRT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Anticancer effect of AZD2461 PARP inhibitor against colon cancer cells carrying wt or dysfunctional p53

Colon cancer is one of the most common cancers, currently treated with traditional chemotherapies or alternative therapies. However, these treatments are still not enough effective and induce several side effects, so that the search of new therapeutic strategies is needed. The use of Poly-(ADP-ribose)-polymerase (PARP) inhibitors, although originally approved against BRCA-1 or BRCA-2 mutated cancers, has been extended, particularly in combination with other treatments, to cure cancers that do not display defects in DNA repair signaling pathways. The role of p53 oncosuppressor in the regulating the outcome of PARP inhibitor treatment remains an open issue. In this study, we addressed this topic by using a well-tolerated PARP 1/2/3 inhibitor, namely AZD2461, against colon cancer cell lines with different p53 status. We found that AZD2461 reduced cell proliferation in wtp53 and p53−/− cancer cells by increasing ROS and DNA damage, while R273H mutant (mut) p53 counteracted these effects. Moreover, AZD2461 improved the reduction of cell proliferation by low dose radiation (IR) in wtp53 cancer cells, in which a down-regulation of BRCA-1 occurred. AZD2461 did not affect cell proliferation of mutp53 colon cancer cells also in combination with low dose radiation, suggesting that only wt p53 or p53 null colon cancer cells could benefit AZD2461 treatment.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1994

Fluid-loading solutions and plasma volume: Astro-ade and salt tablets with water

Fluid loading with salt and water is a countermeasure used after space flight to restore body fluids. However, gastrointestinal side effects have been frequently reported in persons taking similar quantities of salt and water in ground-based studies. The effectiveness of the Shuttle fluid-loading countermeasure (8 gms salt, 0.97 liters of water) was compared to Astro-ade (an isotonic electrolyte solution), to maintain plasma volume (PV) during 4.5 hrs of resting fluid restriction. Three groups of healthy men (n=6) were studied: a Control Group (no drinking), an Astro-ade Group, and a Salt Tablet Group. Changes in PV after drinking were calculated from hematocrit and hemoglobin values. Both the Salt Tablet and Astro-ade Groups maintained PV at 2-3 hours after ingestion compared to the Control Group, which had a 6 percent decline. Side effects (thirst, stomach cramping, and diarrhea) were noted in at least one subject in both the Astro-ade and Salt Tablet Groups. Nausea and vomiting were reported in one subject in the Salt Tablet Group. It was concluded that Astro-ade may be offered as an alternate fluid-loading countermeasure but further work is needed to develop a solution that is more palatable and has fewer side effects.

Fortney, Suzanne M.↗
NASA NTRS2013

Stratospheric Ozone Response in Experiments G3 and G4 of the Geoengineering Model Intercomparison Project (GeoMIP)

Geoengineering with stratospheric sulfate aerosols has been proposed as a means of temporarily cooling the planet, alleviating some of the side effects of anthropogenic CO2 emissions. However, one of the known side effects of stratospheric injections of sulfate aerosols is a decrease in stratospheric ozone. Here we show results from two general circulation models and two coupled chemistry climate models that have simulated stratospheric sulfate aerosol geoengineering as part of the Geoengineering Model Intercomparison Project (GeoMIP). Changes in photolysis rates and upwelling of ozone-poor air in the tropics reduce stratospheric ozone, suppression of the NOx cycle increases stratospheric ozone, and an increase in available surfaces for heterogeneous chemistry modulates reductions in ozone. On average, the models show a factor 20-40 increase of the sulfate aerosol surface area density (SAD) at 50 hPa in the tropics with respect to unperturbed background conditions and a factor 3-10 increase at mid-high latitudes. The net effect for a tropical injection rate of 5 Tg SO2 per year is a decrease in globally averaged ozone by 1.1-2.1 DU in the years 2040-2050 for three models which include heterogeneous chemistry on the sulfate aerosol surfaces. GISS-E2-R, a fully coupled general circulation model, performed simulations with no heterogeneous chemistry and a smaller aerosol size; it showed a decrease in ozone by 9.7 DU. After the year 2050, suppression of the NOx cycle becomes more important than destruction of ozone by ClOx, causing an increase in total stratospheric ozone. Contribution of ozone changes in this experiment to radiative forcing is 0.23 W m-2 in GISS-E2-R and less than 0.1 W m-2 in the other three models. Polar ozone depletion, due to enhanced formation of both sulfate aerosol SAD and polar stratospheric clouds, results in an average 5 percent increase in calculated surface UV-B.

aerosol↗