Manifesto of an ad man

winter 2010Stores mentioned in article (available in MOspace): Q & A: "A man of many words" ; in action: Hogging the stage."Associate Professor Steve Kopcha shares what he's learned since college."Introduction by Sarah Garber ; Excerpt by Steve Kopcha ; Photo by Nicholas Benne

Options for Affordable Fission Surface Power Systems

Fission surface power systems could provide abundant power anywhere on free surface of the moon or Mars. Locations could include permanently shaded regions on the moon and high latitudes on Mars. To be fully utilized; however, fission surface power systems must be safe, have adequate performance, and be affordable. This paper discusses options for the design and development of such systems

Options for Affordable Planetary Fission Surface Power Systems

Nuclear fission systems could serve as "workhorse" power plants for the Vision for Space Exploration. In this context, the "workhorse" power plant is defined as a system that could provide power anywhere on the surface of the moon or Mars, land on the moon using a Robotic Lunar Exploration Program (RLEP)-developed lander, and would be a viable, affordable option once power requirements exceed that which can be provided by existing energy systems

Predicting impacts of chemicals from organisms to ecosystem service delivery: A case study of endocrine disruptor effects on trout

We demonstrate how mechanistic modeling can be used to predict whether and how biological responses to chemicals at (sub)organismal levels in model species (i.e., what we typically measure) translate into impacts on ecosystem service delivery (i.e., what we care about). We consider a hypothetical case study of two species of trout, brown trout (Salmo trutta; BT) and greenback cutthroat trout (Oncorhynchus clarkii stomias; GCT). These hypothetical populations live in a high-altitude river system and are exposed to human-derived estrogen (17α‑ethinyl estradiol, EE2), which is the bioactive estrogen in many contraceptives. We use the individual based model in STREAM to explore how seasonally varying concentrations of EE2 could influence male spawning and sperm quality. Resulting impacts on trout recruitment and the consequences of such for anglers and for the continued viability of populations of GCT (the state fish of Colorado) are explored. in STREAM incorporates seasonally varying river flow and temperature, fishing pressure, the influence of EE2 on species-specific demography, and inter-specific competition. The model facilitates quantitative exploration of the relative importance of endocrine disruption and inter-species competition on trout population dynamics. Simulations predicted constant EE2 loading to have more impacts on GCT than BT. However, increasing removal of BT by anglers can enhance the persistence of GCT and offset some of the negative effects of EE2. We demonstrate how models that quantitatively link impacts of chemicals and other stressors on individual survival, growth, and reproduction to consequences for populations and ecosystem service delivery, can be coupled with ecosystem service valuation. The approach facilitates interpretation of toxicity data in an ecological context and gives beneficiaries of ecosystem services amore explicit role in management decisions. Although challenges remain, this type of approach may be particularly helpful for site-specific risk assessments and those in which trade offs and synergies among ecosystem services need to be considered

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Matter-wave Atomic Gradiometer Interferometric Sensor (MAGIS-100)

MAGIS-100 is a next-generation quantum sensor under construction at Fermilab that aims to explore fundamental physics with atom interferometry over a 100-meter baseline. This novel detector will search for ultralight dark matter, test quantum mechanics in new regimes, and serve as a technology pathfinder for future gravitational wave detectors in a previously unexplored frequency band. It combines techniques demonstrated in state-of-the-art 10-meter-scale atom interferometers with the latest technological advances of the world's best atomic clocks. MAGIS-100 will provide a development platform for a future kilometer-scale detector that would be sufficiently sensitive to detect gravitational waves from known sources. Here we present the science case for the MAGIS concept, review the operating principles of the detector, describe the instrument design, and study the detector systematics.Comment: 65 pages, 18 figure

The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine

Background: The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries. Methods: We modeled common tumor profiling modalities—large (n = 300 genes), medium (n = 48 genes), and small (n = 15 genes) panels—using clinical whole exomes (WES) from 157 patients with lung or colon adenocarcinoma. We created a tumor-only analysis algorithm to assess germline false positive rates, the impact of patient ancestry on tumor-only results, and neoantigen detection. Results: After optimizing a germline filtering strategy, the germline false positive rate with tumor-only large panel sequencing was 14 % (144/1012 variants). For patients whose tumor-only results underwent molecular pathologist review (n = 91), 50/54 (93 %) false positives were correctly interpreted as uncertain variants. Increased germline false positives were observed in tumor-only sequencing of non-European compared with European ancestry patients (p < 0.001; Fisher’s exact) when basic germline filtering approaches were used; however, the ExAC database (60,706 germline exomes) mitigated this disparity (p = 0.53). Matched and unmatched large panel mutational load correlated with WES mutational load (r2 = 0.99 and 0.93, respectively; p < 0.001). Neoantigen load also correlated (r2 = 0.80; p < 0.001), though WES identified a broader spectrum of neoantigens. Small panels did not predict mutational or neoantigen load. Conclusions: Large tumor-only targeted panels are sufficient for most somatic variant identification and mutational load prediction if paired with expanded germline analysis strategies and molecular pathologist review. Paired germline sequencing reduced overall false positive mutation calls and WES provided the most neoantigens. Without patient-matched germline data, large germline databases are needed to minimize false positive mutation calling and mitigate ethnic disparities. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0333-9) contains supplementary material, which is available to authorized users

Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer

Background Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term “Directed Evolution” for creating highly potent oncolytic viruses. Methodology/Principal Findings Taking the “Directed Evolution” approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2–3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. Conclusions/Significance Using the “Directed Evolution” methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a &gt;2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2