Metabolic Dependencies in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a long-term survival rate under 10%. Available cytotoxic chemotherapies have significant side effects, and only marginal therapeutic efficacy. FDA approved drugs currently used against PDA target DNA metabolism and DNA integrity. However, alternative metabolic targets beyond DNA may prove to be much more effective. PDA cells are forced to live within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. Thus, PDA cells must possess biochemical flexibility in order to adapt to austere conditions. A better understanding of the metabolic dependencies required by PDA to survive and thrive within a harsh metabolic milieu could reveal specific metabolic vulnerabilities. These molecular requirements can then be targeted therapeutically, and would likely be associated with a clinically significant therapeutic window since the normal tissue is so well-perfused with an abundant nutrient supply. Recent work has uncovered a number of promising therapeutic targets in the metabolic domain, and clinicians are already translating some of these discoveries to the clinic. In this review, we highlight mitochondria metabolism, non-canonical nutrient acquisition pathways (macropinocytosis and use of pancreatic stellate cell-derived alanine), and redox homeostasis as compelling therapeutic opportunities in the metabolic domain

Evaluation of Agricultural Land Cover Representations on Regional Climate Model Simulations in the Brazilian Cerrado

Examining interactions between large-scale land cover and land use change and regional climate in areas undergoing dynamic land transformations, like the Brazilian Cerrado, is crucial for understanding tradeoffs between human needs and ecosystem services. Yet regional climate models often do not include accurate land cover data of these complex landscapes. We use National Center for Atmospheric Research’s Weather Research and Forecasting (WRF) model coupled to the Noah-Multiparameterization (Noah-MP) land surface model to run 10-year climate simulations across Brazil to assess (1) whether an accurate, regionally validated land cover data set with two, new agricultural land cover classifications improves model simulation results; (2) the ability of Noah-MP’s dynamic vegetation option to model vegetation growth; and (3) the sensitivity of the model output to scale. The results of the simulations with the updated land surface perform better over intensive agricultural areas for precipitation, evapotranspiration, and temperature, especially during the wet-to-dry season transition months. Evapotranspiration is overestimated during the start of the rainy season across all model simulations, which is likely due to the soil moisture model. We also find that using the Noah-MP dynamic vegetation significantly degrades agricultural leaf area index phenology simulations in Brazilian agricultural regions. Lastly, improving the model’s resolution did not improve model output when compared to observational data. Incorporating more accurate representations of the landscape into regional climate models is essential for quantifying potential changes in climatological seasonality in dynamic, human-modified regions and making informed land use decisions

Moving Toward a Personalized Approach for Cancer a Scientific Discussion: Mechanisms of Chemoresistance in Pancreatic Cancer

*Supported by the Gail V. Coleman – Kenneth M. Bruntel Pancreatic Research Fund PowerPoint slides. No audio

Brazilian Maize Yields Negatively Affected by climate after Land Clearing

To date, over 50% of the Brazilian Cerrado has been cleared predominantly for 11 agropastoral purposes. Here, we use the Weather Research and Forecasting model to run 15- 12 year climate simulations across Brazil with six land-cover scenarios: 1) before extensive land 13 clearing; 2) observed in 2016; 3) Cerrado replaced with single-cropped (soy) agriculture; 4) 14 Cerrado replaced with double-cropped (soy-maize) agriculture; 5) eastern Amazon replaced 15 with single-cropped agriculture; and 6) eastern Amazon replaced with double-cropped 16 agriculture. All land-clearing scenarios (2-6) contain significantly more growing season days 17 with temperatures that exceed critical temperature thresholds for maize. Evaporative fraction 18 significantly decreases across all land-clearing scenarios. Altered weather reduces maize yields 19 between 6–8%, when compared to the before extensive land clearing scenario; however, soy 20 yields were not significantly affected. Our findings provide evidence that land clearing has 21 degraded weather in the Brazilian Cerrado, undermining one of the main reasons for land 22 clearing: rainfed crop production

Patterns of nutrient export for a typical non-point source, Meadowbrook Farm, Madison County, Kentucky

Excess nutrients are found in watersheds originating from active farmland often causing poor water quality and eutrophication in natural waters. Use of fertilizer and animal husbandry can contaminate both surface water and groundwater. Eastern Kentucky University’s Meadowbrook Farm raises crops and livestock and is typical of farms that contribute excess nutrient contaminants to watersheds as non-point sources. An instrumented weir is positioned within a key sub-watershed of the Farm that empties into Muddy Creek, a tributary of the Kentucky River. This drainage is the largest outlet from the Farm that is representative of the Farm’s collective activities. We measured flow and nutrient concentration (orthophosphate, PO43-; nitrate, NO3-; and ammonium, NH4+) over the weir to ascertain flow rates, nutrient export rates, and overall nutrient export. We concentrate on patterns of nutrient export during a single rainy period from 22 to 25 June 2017, which encompasses the passage of the remnants of tropical storm Cindy. In addition, baseline samples were obtained during drier periods throughout that summer. Various nutrients respond differently to storm flow. Dissolved phosphate mirrors the flow hydrograph showing peak concentrations of 0.5, 0.8, 1.2, and 1.0 mg/L correlative with 4 distinct instances of peak flow. Nitrate concentration spikes sharply to ~3.0 mg/L during initial runoff but then quickly decreases and maintains constant values between 1.0 and 1.5 mg/L. Ammonium values are highest, just under 2 mg/L, before initial flow over the weir and then decrease to show sporadic values between 0.1 and 0.6 mg/L, apparently independent of discharge

Nutrient export from a proximal intermittent stream draining EKU Meadowbrook Farm, Madison County, Kentucky

Agricultural activities contribute significant amounts of nutrients that contaminate surface and subsurface water. Eastern Kentucky University (EKU) Meadowbrook Farm (Madison County, Kentucky) seeks to decrease its export of nutrients to Muddy Creek using sequestration techniques. The first step in the overall process is to determine nutrient export at present, before sequestration efforts take place. Here we estimate the export of phosphate, nitrate, and ammonium during Tropical Storm Cindy (July 22 to 24, 2017) from a proximal, intermittent stream, named the BRC. This stream drains a representative portion the Farm, receiving water from a dairy complex, pasture, and cropland. To estimate nutrient export, both discharge and nutrient concentration must be determined. We have built a V-notched weir across the BRC drainage equipped with a datalogger that measures water elevation behind the dam, and an autosampler that captures water samples during rain events. Water level and discharge over the dam are proportional, so that discharge can be calculated during rain events. Nutrient concentration is measured for each water sample using accepted colorimetric methods: ascorbic acid (phosphate), cadmium reduction (nitrate), and sodium hypochlorite (ammonium). Once discharge and nutrient concentrations are measured for the rain event, total nutrient mass can be calculated from the resultant curves (Fig. 1). Discharge and concentration data were parsed into 30-second time steps over the course of the entire, 72-hour rain event, and we used a cubic spline application (grafted into MS Excel) to produce a continuous function for each parameter. The area under the discharge and concentration curves yielded total solute mass for the Cindy event. Based on these data and using the cubic spline technique, we estimate that the export of phosphorus was 3.1 kg P occurring as dissolved orthophosphate, and 6.3 kg N occurring as dissolved nitrate (5.3 kg) and ammonium (1.0 kg) during Cindy. We also intend to determine the amount of total phosphorus (orthophosphate, other forms of dissolved phosphorus, P contained within dissolved organics, and P adsorbed onto fine particulates) exported during Cindy, as well as estimating nutrient export for five other rain events captured during 2017

Total and extreme precipitation changes over the Northeastern United States

The northeastern United States has experienced a large increase in precipitation over recent decades. Annual and seasonal changes of total and extreme precipitation from station observations in the Northeast were assessed over multiple time periods spanning 1901-2014. Spatially averaged, both annual total and extreme precipitation across the Northeast increased significantly since 1901, with changepoints occurring in 2002 and 1996, respectively. Annual extreme precipitation experienced a larger increase than total precipitation; extreme precipitation from 1996 to 2014 is 53% higher than from 1901 to 1995. Spatially, coastal areas receive more total and extreme precipitation on average, but increases across the changepoints are distributed fairly uniformly across the domain. Increases in annual total precipitation across the 2002 changepoint are driven by significant total precipitation increases in fall and summer, while increases in annual extreme precipitation across the 1996 changepoint are driven by significant extreme precipitation increases in fall and spring. The ability of gridded observed and reanalysis precipitation data to reproduce station observations was also evaluated. Gridded observations perform well in reproducing averages and trends of annual and seasonal total precipitation, but extreme precipitation trends show significantly different spatial and domain-averaged trends than station data. The North American Regional Reanalysis generally underestimates annual and seasonal total and extreme precipitation means and trends relative to station observations, and also shows substantial differences in the spatial pattern of total and extreme precipitation trends within the Northeast

Impacts of projected climate change over the Lake Champlain basin in Vermont

The Lake Champlain basin is a critical ecological and socioeconomic resource of the northeastern United States and southern Quebec, Canada. While general circulation models (GCMs) provide an overview of climate change in the region, they lack the spatial and temporal resolution necessary to fully anticipate the effects of rising global temperatures associated with increasing greenhouse gas concentrations. Observed trends in precipitation and temperature were assessed across the Lake Champlain basin to bridge the gap between global climate change and local impacts. Future shifts in precipitation and temperature were evaluated as well as derived indices, including maple syrup production, days above 32.2°C (90°F), and snowfall, relevant to managing the natural and human environments in the region. Four statistically downscaled, biascorrected GCM simulations were evaluated from the Coupled Model Intercomparison Project phase 5 (CMIP5) forced by two representative concentration pathways (RCPs) to sample the uncertainty in future climate simulations. Precipitation is projected to increase by between 9.1 and 12.8mmyr-1 decade-1 during the twenty-first century while daily temperatures are projected to increase between 0.43° and 0.49°C decade-1. Annual snowfall at six major ski resorts in the region is projected to decrease between 46.9%and 52.4%by the late twenty-first century. In the month of July, the number of days above 32.2°C in Burlington, Vermont, is projected to increase by over 10 days during the twenty-first century. © 2014 American Meteorological Society

A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2.

BACKGROUND: Variation in an individual\u27s genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of-function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. STUDY DESIGN: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, and the other genotypes were grouped as wild-type or heterozygous. Genotype distributions of each SNP were analyzed for Hardy-Weinberg deviation. A genotype frequency set from the 1000 Genomes Project (n = 99) was used as a genetic control for genotype distribution comparisons. RESULTS: A significant 2-fold increase in the overall prevalence of the Y359Stop homozygous genotype compared with the expected Hardy-Weinberg equilibrium was noted (p \u3c 0.05). Familial pancreatic cancer was noted in 15 cases (19%) and comparison of the FPC cohort set to the genetic control set showed a 3-fold increase in Y359Stop homozygous rates (p = 0.054). Overall in our cohort, the homozygous genotype group was associated with increased risk of FPC (odds ratio 5.4; 95% CI 1.6 to 17.6; p \u3c 0.01). Sex, age at diagnosis, and history of tobacco use were not found to be significantly associated with FPC. CONCLUSIONS: Our preliminary data suggest a strong association between the IDO2 inactivating Y359Stop SNP and an increased risk of FPC when compared with the control group. Future studies will evaluate the value of IDO2 genotyping as a prognostic, early detection marker for pancreatic ductal adenocarcinoma and a predictive marker for novel immune checkpoint therapies