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

Establishing macroecological trait datasets: digitalization, extrapolation, and validation of diet preferences in terrestrial mammals worldwide

Ecological trait data are essential for understanding the broad-scale distribution of biodiversity and its response to global change. For animals, diet represents a fundamental aspect of species’ evolutionary adaptations, ecological and functional roles, and trophic interactions. However, the importance of diet for macroevolutionary and macroecological dynamics remains little explored, partly because of the lack of comprehensive trait datasets. We compiled and evaluated a comprehensive global dataset of diet preferences of mammals (“MammalDIET”). Diet information was digitized from two global and cladewide data sources and errors of data entry by multiple data recorders were assessed. We then developed a hierarchical extrapolation procedure to fill-in diet information for species with missing information. Missing data were extrapolated with information from other taxonomic levels (genus, other species within the same genus, or family) and this extrapolation was subsequently validated both internally (with a jack-knife approach applied to the compiled species-level diet data) and externally (using independent species-level diet information from a comprehensive continentwide data source). Finally, we grouped mammal species into trophic levels and dietary guilds, and their species richness as well as their proportion of total richness were mapped at a global scale for those diet categories with good validation results. The success rate of correctly digitizing data was 94%, indicating that the consistency in data entry among multiple recorders was high. Data sources provided species-level diet information for a total of 2033 species (38% of all 5364 terrestrial mammal species, based on the IUCN taxonomy). For the remaining 3331 species, diet information was mostly extrapolated from genus-level diet information (48% of all terrestrial mammal species), and only rarely from other species within the same genus (6%) or from family level (8%). Internal and external validation showed that: (1) extrapolations were most reliable for primary food items; (2) several diet categories (“Animal”, “Mammal”, “Invertebrate”, “Plant”, “Seed”, “Fruit”, and “Leaf”) had high proportions of correctly predicted diet ranks; and (3) the potential of correctly extrapolating specific diet categories varied both within and among clades. Global maps of species richness and proportion showed congruence among trophic levels, but also substantial discrepancies between dietary guilds. MammalDIET provides a comprehensive, unique and freely available dataset on diet preferences for all terrestrial mammals worldwide. It enables broad-scale analyses for specific trophic levels and dietary guilds, and a first assessment of trait conservatism in mammalian diet preferences at a global scale. The digitalization, extrapolation and validation procedures could be transferable to other trait data and taxa

Mammal predator and prey species richness are strongly linked at macroscales

Predator-prey interactions play an important role for species composition and community dynamics at local scales, but their importance in shaping large-scale gradients of species richness remains unexplored. Here, we use global range maps, structural equation models (SEM), and comprehensive databases of dietary preferences and body masses of all terrestrial, non-volant mammals worldwide, to test whether (1) prey bottom-up or predator top-down relationships are important drivers of broad-scale species richness gradients once the environment and human influence have been accounted for, (2) predator-prey richness associations vary among biogeographic regions, and (3) body size influences large-scale covariation between predators and prey. SEMs including only productivity, climate, and human factors explained a high proportion of variance in prey richness (R2 = 0.56) but considerably less in predator richness (R2 = 0.13). Adding predator-to-prey or prey-topredator paths strongly increased the explained variance in both cases (prey R2 = 0.79, predator R2 = 0.57), suggesting that predator-prey interactions play an important role in driving global diversity gradients. Prey bottom-up effects prevailed over productivity, climate, and human influence to explain predator richness, whereas productivity and climate were more important than predator top-down effects for explaining prey richness, although predator top-down effects were still significant. Global predator-prey associations were not reproduced in all regions, indicating that distinct paleoclimate and evolutionary histories (Africa and Australia) may alter species interactions across trophic levels. Stronger crosstrophic- level associations were recorded within categories of similar body size (e.g., large prey to large predators) than between them (e.g., large prey to small predators), suggesting that mass-related energetic and physiological constraints influence broad-scale richness links, especially for large-bodied mammals. Overall, our results support the idea that trophic interactions can be important drivers of large-scale species richness gradients in combination with environmental effects. © 2013 by the Ecological Society of America

Quantification and expert evaluation of evidence for chemopredictive biomarkers to personalize cancer treatment.

Predictive biomarkers have the potential to facilitate cancer precision medicine by guiding the optimal choice of therapies for patients. However, clinicians are faced with an enormous volume of often-contradictory evidence regarding the therapeutic context of chemopredictive biomarkers.We extensively surveyed public literature to systematically review the predictive effect of 7 biomarkers claimed to predict response to various chemotherapy drugs: ERCC1-platinums, RRM1-gemcitabine, TYMS-5-fluorouracil/Capecitabine, TUBB3-taxanes, MGMT-temozolomide, TOP1-irinotecan/topotecan, and TOP2A-anthracyclines. We focused on studies that investigated changes in gene or protein expression as predictors of drug sensitivity or resistance. We considered an evidence framework that ranked studies from high level I evidence for randomized controlled trials to low level IV evidence for pre-clinical studies and patient case studies.We found that further in-depth analysis will be required to explore methodological issues, inconsistencies between studies, and tumor specific effects present even within high evidence level studies. Some of these nuances will lend themselves to automation, others will require manual curation. However, the comprehensive cataloging and analysis of dispersed public data utilizing an evidence framework provides a high level perspective on clinical actionability of these protein biomarkers. This framework and perspective will ultimately facilitate clinical trial design as well as therapeutic decision-making for individual patients

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

Effect of humidity on insensible weight loss, total vaporized moisture, and surface temperature in cattle.

Missouri Agricultural Experiment Station and the United States Department of Agriculture cooperating assisted by the Office of Naval Research."This bulletin is a report from the Department of Dairy Husbandry, research project No. 100, and Agricultural Engineering, research project No. 66 entitled 'Influence of climate factor on productivity'"--P. [2].Includes bibliographical references

Structural Implications for Selective Targeting of PARPs.

Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that use NAD(+) as a substrate to synthesize polymers of ADP-ribose (PAR) as post-translational modifications of proteins. PARPs have important cellular roles that include preserving genomic integrity, telomere maintenance, transcriptional regulation, and cell fate determination. The diverse biological roles of PARPs have made them attractive therapeutic targets, which have fueled the pursuit of small molecule PARP inhibitors. The design of PARP inhibitors has matured over the past several years resulting in several lead candidates in clinical trials. PARP inhibitors are mainly used in clinical trials to treat cancer, particularly as sensitizing agents in combination with traditional chemotherapy to reduce side effects. An exciting aspect of PARP inhibitors is that they are also used to selectivity kill tumors with deficiencies in DNA repair proteins (e.g., BRCA1/2) through an approach termed synthetic lethality. In the midst of the tremendous efforts that have brought PARP inhibitors to the forefront of modern chemotherapy, most clinically used PARP inhibitors bind to conserved regions that permits cross-selectivity with other PARPs containing homologous catalytic domains. Thus, the differences between therapeutic effects and adverse effects stemming from pan-PARP inhibition compared to selective inhibition are not well understood. In this review, we discuss current literature that has found ways to gain selectivity for one PARP over another. We furthermore provide insights into targeting other domains that make up PARPs, and how new classes of drugs that target these domains could provide a high degree of selectivity by affecting specific cellular functions. A clear understanding of the inhibition profiles of PARP inhibitors will not only enhance our understanding of the biology of individual PARPs, but may provide improved therapeutic options for patients

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3\u27UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic