Metabolic Regulation of Ferroptosis in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is a notoriously deadly disease having the lowest 5-year survival rate of any major cancer, owing to a lack of effective therapeutic options. A growing body of evidence demonstrates that PDAs reprogram their metabolism to support growth and survival in response to a harsh metabolic tumor environment. This work studies the hypothesis that metabolism can reveal novel therapeutic targets. Uncovering novel nutrient vulnerabilities could provide new ways to target PDA selectively. The goals of this work were two-fold. First, we developed analytical methods to identify metabolic changes in PDA and other biological samples. Employing mass spectrometry metabolomics, we profiled over two hundred metabolites in a single experiment across heterogeneous biological samples and experimental conditions. A meta-analysis of these metabolomics studies revealed insights into metabolite reproducibility, providing analytical benchmarks for quality control. Moreover, through systematic analysis we identified stable and dynamic metabolites, where dynamic metabolites play numerous roles in modulating gene expression and signaling. Together, this work provides benchmarks for metabolomics method development and robust analytical frameworks. Second, we examined nutrient vulnerabilities in PDA to identify novel therapeutic opportunities. We found that pancreatic cancer cells were highly sensitive to cystine deprivation. Cystine was required for the biosynthesis of two versatile redox co-factors, glutathione and coenzyme-A. Starving pancreatic cancer cells and tumors from cysteine triggered ferroptosis: an oxidative, iron-dependent, non-apoptotic form of cell death. Inhibiting cystine metabolism was well tolerated in mice and showed substantial anti-tumor activity, suggesting a new therapeutic strategy for PDA. In addition to identifying cystine as a metabolic vulnerability, we previously described that pancreatic cancers depend on a cytosolic aspartate aminotransaminase (GOT1)-dependent pathway for redox balance. Inhibiting GOT1 slowed the growth of PDA cells and tumors. We sought to identify metabolic dependencies induced by GOT1 inhibition as a strategy to kill PDAs selectively. We found cystine, glutathione, and lipid antioxidant function were metabolic susceptibilities following GOT1 suppression. Targeting these metabolic nodes triggered ferroptosis in synergy with GOT1 and delayed tumor growth. This effect was due to labile iron release, which augments ferroptosis sensitivity. Together, this work describes the development of mass spectrometry metabolomics tools and reveals how metabolism and ferroptosis are linked. This work presents new methods to study ferroptosis in diverse model systems, reconciling long-standing limitations in the field. We identify several metabolic nodes governing ferroptosis susceptibility, building upon the notion that ferroptosis is a metabolically-coupled form of cell death. Finally, we discuss several strategies to harness ferroptosis for therapy that could lead to novel treatments for PDA.PHDChemical BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163213/1/dmkremer_1.pd

Income Distribution Dynamics With Endogenous Fertility

Developing countries with highly unequal income distributions, such as Brazil or South Africa, face an uphill battle in reducing inequality. Educated workers in these countries have a much lower birth rate than uneducated workers. Assuming children of educated workers are more likely to become educated, this fertility differential increaases the proportion of unskilled workers, reducing their wages, and thus their opportunity cost of having children, creating a vicious cycle. A model incorporating this effect generates multiple stedy-state levels of inequality, suggesting that in some circumstances, temporarily increasing access to educational opportunities could permanently reduce inequality. Empirical evidence suggests that the fertility differential between the educated and uneducated is greater in less equal countries, consistent with the model. An earlier version of this paper was published in the AEA Papers and Proceedings, May 1999 and is also available here

Quantitative trait dissection analysis in Eucalytus using RAPD markers: 2. Linkage disequilibrium in a factorial design between E. urophylle and E. Grandis.

International audience.4 13 x 13 factorial design between E. rlr.opllj,llu and E. grmclis, comprising 87 full-sib families, was used to assess the relationships between RAPD marker frequency classes obtained from parental genotypes and the interspecific additive mean (IAM) of the hybrid progeny. For any markcr showing a significant association, the cumulative number of the " present band " allele in the parents was significantly correlated either positively or negatively, with the IAM of the traits studied: i.e. volume, stem taper and wood quality. We discuss the potential origin of such correlations in terms of linkage disequilibrium between QTL allele and marker allele. We also examine the possible use of such information, firstly in order to select the parents for further generations of breeding, and secondly in ordcr to choose thc hybrid families in which QTAs of specific value could be detected and uscd to identify the best trees to be vegetatively propagated for the production of clonal variety

Description of the Efficacy and Safety of Three New Biologics in the Treatment of Rheumatoid Arthritis

English articles on abatacept, golimumab, and tocilizumab in rheumatoid arthritis published between 2002 and 2009 were reviewed systematically. All randomized clinical trials, open-label extensions, meta-analyses, and reviews were examined. There were thirteen articles on abatacept, four on golimumab, and seven on tocilizumab. All three drugs were effective in methotrexate-naïve, methotrexate-incomplete responders, and tumor-necrosis-factor-failure rheumatoid arthritis patients. Of the three, only abatacept has been tested in a head-to-head trial with infliximab, in which it was found to be equivalent to infliximab. Golimumab resulted in a more modest improvement than the others in methotrexate-naïve patients, although no direct comparisons among the three drugs were possible or appropriate. Descriptive analysis of adverse events showed that patients receiving abatacept, golimumab, and tocilizumab were subject to more adverse events than controls overall, as expected. In the abatacept studies, a few cases of tuberculosis, more cardiovascular events and gastrointestinal bleedings and more basal cell carcinoma were seen. Golimumab was associated with more skin rashes and pneumonia, while tocilizumab was associated with increased lipids, more liver-function abnormalities, and neutropenia. These new medications are useful additions to the rheumatologic armamentarium and represent greater convenience (golimumab) or different mechanisms of action (abatacept and tocilizumab) than tumor-necrosis-factor inhibitors for treating rheumatoid arthritis. As expected, some adverse events occur when using these drugs and patients need to be watched carefully

ESAG Comunidade: Desenvolvimento Comunitário, Cidadania e Redes Sociais.

Trabalho apresentado no 31º SEURS - Seminário de Extensão Universitária da Região Sul, realizado em Florianópolis, SC, no período de 04 a 07 de agosto de 2013 - Universidade Federal de Santa Catarina.O Programa ESAG Comunidade tem por objetivo fortalecer os laços entre a ESAG/UDESC e a comunidade, por meio do apoio a organizações da sociedade civil, do fortalecimento da rede social local e da promoção da cidadania e do desenvolvimento comunitário. O programa se estrutura em três eixos complementares. O primeiro refere-se ao apoio às Organizações da Sociedade Civil (OSCs) e aos investidores sociais, por meio de ações de formação que apoiam o desenvolvimento institucional das OSCs e a cultura do Investimento Social Privado, ações realizadas no Projeto Redes Sociais. O segundo eixo refere-se ao fomento à participação cidadã por meio do projeto Cidadania é Direito. O projeto oferece à comunidade a construção de um raciocínio jurídico, mediante o aprendizado de noções de direitos, do modo de garanti-los, contribuindo para a materialização do acesso à Justiça. Finalmente, o terceiro eixo corresponde ao projeto Desenvolvimento Comunitário e inclui o incentivo à participação cívica e ao exercício da cidadania dos membros da comunidade acadêmica e sua interação com outros atores, buscando a sua mobilização social. Somente no âmbito do ensino, o projeto mobilizou cerca de 120 alunos em suas ações, atingindo a diversas comunidades e organizações comunitárias, com eventos, ações educativas e projetos de intervenção comunitária

Single-single gravitational-wave captures in globular clusters: Eccentric deci-Hertz sources observable by DECIGO and Tian-Qin

We study the formation rate of binary black hole mergers formed through gravitational-wave emission between unbound, single black holes in globular clusters. While the formation of these binaries in very dense systems such as galactic nuclei has been well studied, we show here that this process can operate in lower-density stellar systems as well, forming binaries at a rate similar to other proposed pathways for creating eccentric mergers. Recent advances in post-Newtonian cluster dynamics indicate that a large fraction of dynamically-assembled binary black holes merge inside their host clusters during weak and strong binary-single and binary-binary interactions, and that these systems may retain measurable eccentricities as they travel through the LIGO and LISA sensitivity bands. Using an analytic approach to modeling binary black holes from globular clusters, we show that the formation of merging binaries from previously unbound black holes can operate at a similar rate to mergers forming during strong binary encounters, and that these binaries inhabit a unique region of the gravitational-wave frequency space which can be identified by proposed deci-Hertz space-based detectors.Comment: 16 pages, 5 figures. Accepted version (PRD

Income-distribution Dynamics with Endogenous Fertility

Developing countries with highly unequal income distributions, such as Brazil or South Africa, face an uphill battle in reducing inequality. Educated workers in these countries have a much lower birthrate than uneducated workers. Assuming children of educated workers are more likely to become educated, this tends to increase the proportion of unskilled workers, reducing their wages, and thus their opportunity cost of having children, creating a vicious cycle. A model incorporating this effect generates multiple steady-state levels of inequality, suggesting that in some circumstances, temporarily increasing access to educational opportunities could permanently reduce inequality. Empirical evidence suggests that the fertility differential between the educated and uneducated is greater in less equal countries, consistent with the model.

A comparison between Poisson and zero-inflated Poisson regression models with an application to number of black spots in Corriedale sheep

Dark spots in the fleece area are often associated with dark fibres in wool, which limits its competitiveness with other textile fibres. Field data from a sheep experiment in Uruguay revealed an excess number of zeros for dark spots. We compared the performance of four Poisson and zero-inflated Poisson (ZIP) models under four simulation scenarios. All models performed reasonably well under the same scenario for which the data were simulated. The deviance information criterion favoured a Poisson model with residual, while the ZIP model with a residual gave estimates closer to their true values under all simulation scenarios. Both Poisson and ZIP models with an error term at the regression level performed better than their counterparts without such an error. Field data from Corriedale sheep were analysed with Poisson and ZIP models with residuals. Parameter estimates were similar for both models. Although the posterior distribution of the sire variance was skewed due to a small number of rams in the dataset, the median of this variance suggested a scope for genetic selection. The main environmental factor was the age of the sheep at shearing. In summary, age related processes seem to drive the number of dark spots in this breed of sheep

Pasture Conditions at the Initiation of Grazing to Optimize Forage Productivity: A Progress Report

To determine environmental, soil, and sward effects at the initiation of cattle grazing in the spring on seasonal (forage accumulated during the grazing season) and cumulative (seasonal + initial forage mass) forage accumulation (FA), 15 commercial cow-calf producers from southern Iowa were selected by historical initial grazing date. At grazing initiation, twelve .25-m2 samples were hand-clipped from each pasture and sward heights (SH) measured with a falling plane meter (4.8 kg/m2) to determine initial forage mass. At each location, soil temperature and load bearing capacity (LBC) were measured and a soil sample was collected to measure pH and moisture, P, and K concentrations. Cumulative degree-days (base=3.85°C) and precipitation at grazing initiation were calculated from NOAA records. At the beginning of each month, at least three grazing exclosures were placed on each grazed pasture to determine monthly FA. SH in each exclosure was recorded, and a .25-m2 forage sample was hand-clipped proximate to each exclosure. At the end of each month, SH was recorded and .25-m2 hand-clipped forage samples from inside exclosures were obtained. In linear regressions, cumulative and seasonal SH increased with greater soil P (r2=.5049 and .5417), soil K (r2=.4675 and .4397), and initial forage mass (r2=.1984 and .2801). Seasonal SH increased with earlier initial grazing dates (r2=.1996) and less accumulated degree-days (r2=.2364). Cumulative and seasonal FA increased with earlier initial grazing dates (r2=.2106 and .3744), lower soil temperatures (r2=.2617 and.2874), and greater soil P (r2=.3489 and .2598). Cumulative FA increased with greater soil K (r2=.4675). In quadratic regressions, cumulative and seasonal SH were correlated to soil P (r2=.6310 and .5310) and soil K (r2=.5095 and.4401). Cumulative and seasonal FA were correlated to degree days (r2=.3630 and.4013) and initial grazing date (r2=.3425 and .4088). Cumulative FA was correlated to soil P (r2=.3539), and seasonal FA was correlated to soil moisture (r2=.3688)

The role of leverage in the asymmetric valuation of dividends

vi, 36 leaves ; 29 cmFuller and Goldstein (2004) find that dividend payments are more valuable in down markets than in up markets. This research extends this study to determine whether the asymmetry in valuing dividend signals is influenced by debt financing. This is essential since firms with high debt financing are more likely to be affected by down markets than those with low debt financing. Consistent with this, the results show firms with greater indebtedness experience greater declines in returns during down markets. This decline, however, was observed to be mitigated by the payment of dividends, with the greatest improvement in returns concentrated with the most highly indebted firms. These results are robust to size, beta, and book-to-market values