Dietary alterations modulate the microRNA 29/30 and IGF-1/AKT signaling axis in breast Cancer liver metastasis.

Background: Metastatic cancer is incurable and understanding the molecular underpinnings is crucial to improving survival for our patients. The IGF-1/Akt signaling pathway is often impaired in cancer leading to its progression and metastases. Diet modification is known to alter the IGF-1/Akt pathway and affect the expression of microRNA involved in tumor initiation, growth and metastases. Liver metastases are one of the most common type of metastases in breast and colon cancer. In the present study, we looked at the effect of diet modification on the expression of microRNA in normal liver and liver with breast cancer metastases using in vivo model. Methodology: 6-month-old C57BL/6 J mice were put on either an ad libitum (AL) diet, or 40% calorie restricted (CR) diet or were fasted for 24 h (FA) before sacrifice. MicroRNA array analysis, western blot and qRT-PCR were performed using liver tissue to compare the treatment groups. A breast cancer model was also used to study the changes in microRNA expression in liver of a group of BALB/c mice orthotopically injected with 4 T1 cells in the mammary fat pad, put on either an AL or 30% CR diet. Liver and primary tumor tissues were used to perform qRT-PCR to compare the treatment groups. Results: MicroRNA array analysis showed significant changes in miRNA expression in both CR and FA conditions in normal liver. Expression of miR-29 and miR-30 family members was increased in both CR and FA. Western blot analysis of the normal liver tissue showed that CR and FA downregulated the IGF-1/Akt pathway and qRT-PCR showed that the expression of miR-29b, miR-29c, miR-30a and miR-30b were increased with CR and FA. Liver tissue collected from mice in the breast cancer model showed an increase in expression of miR-29b, miR-29c and miR-30b while tumor tissue showed increased expression of miR-29c, miR-30a and miR-30b. Discussion: Members of the miR-29 family are known to target and suppress IGF-1, while members of the miR-30 family are known to target and suppress both IGF-1 and IGF-1R. In the present study, we observe that calorie restriction increased the expression of miR-29 and miR-30 in both the normal liver as well as the liver with breast cancer metastases. These findings suggest that dietary alterations may play a role in the treatment of liver metastasis, which should be evaluated further

Pilot Study of Endurance Runners and Brain Responses Associated with Delay Discounting

International Journal of Exercise Science 10(5): 690-701, 2017. High levels of endurance training have been associated with potentially negative health outcomes and addictive-like symptoms such as exercise in the presence of injury and higher levels of impulsivity. This pilot study examined the relationships among self-report measures of addictive symptoms related to exercise and behavioral and neural measures of impulsivity in endurance runners. We hypothesized endurance runners would have increased preference for immediate rewards and greater activation of cognitive control regions when making decisions involving delayed rewards. Twenty endurance runners (at least 20 miles/week) were recruited to undergo measures of self-report exercise addiction symptoms, impulsive decision-making (delay discounting) and functional magnetic resonance imaging (fMRI). During behavioral and fMRI examinations, participants chose between a small hypothetical amount of money given immediately ($0 – 100) compared to a larger hypothetical amount of money ($100) given after a delay (2-12 weeks). On half of the trials participants were instructed that if they chose the delayed reward they would not be able to exercise during the delay period. Eighteen participants were included in the analysis. Results indicated that 94% of endurance runners reported high levels of exercise addiction symptoms, and 44% were “at-risk” for exercise addiction. In addition, endurance runners demonstrated increased preference for immediately available compared to delayed rewards (p \u3c 0.001) and greater recruitment of cognitive control regions (dorsomedial prefrontal cortex and anterior cingulate) when making decisions involving rewards when exercise was delayed (p \u3c 0.05). Together, these results indicate that endurance runners not only report addictive symptoms related to exercise, but also demonstrate addictive-like behaviors

Molecular Hydrogen in the FUSE Translucent Lines of Sight: The Full Sample

We report total abundances and related parameters for the full sample of the FUSE survey of molecular hydrogen in 38 translucent lines of sight. New results are presented for the "second half" of the survey involving 15 lines of sight to supplement data for the first 23 lines of sight already published. We assess the correlations between molecular hydrogen and various extinction parameters in the full sample, which covers a broader range of conditions than the initial sample. In particular, we are now able to confirm that many, but not all, lines of sight with shallow far-UV extinction curves and large values of the total-to-selective extinction ratio, $R_V$ = $A_V$ / $E(B-V)$ -- characteristic of larger than average dust grains -- are associated with particularly low hydrogen molecular fractions ($f_{\rm H2}$). In the lines of sight with large $R_V$, there is in fact a wide range in molecular fractions, despite the expectation that the larger grains should lead to less H$_2$ formation. However, we see specific evidence that the molecular fractions in this sub-sample are inversely related to the estimated strength of the UV radiation field and thus the latter factor is more important in this regime. We have provided an update to previous values of the gas-to-dust ratio, $N$(H$_{\rm tot}$)/$E(B-V)$, based on direct measurements of $N$(H$_2$) and $N$(H I). Although our value is nearly identical to that found with Copernicus data, it extends the relationship by a factor of 2 in reddening. Finally, as the new lines of sight generally show low to moderate molecular fractions, we still find little evidence for single monolithic "translucent clouds" with $f_{\rm H2}$ $\sim$ 1.Comment: 35 pages, 5 tables, 7 figures, accepted for publication in The Astrophysical Journal Supplements Serie

Caloric restriction augments radiation efficacy in breast cancer.

Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC

Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications

Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (−)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (−)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (±)-, (+)-, and (−)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT2B receptor and were partial to full agonists at the 5-HT2B receptor. Conclusions—Our data imply that activation of 5-HT2B receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT2B receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT2B receptors

Testing the Dark Matter Interpretation of the DAMA/LIBRA Result with Super-Kamiokande

We consider the prospects for testing the dark matter interpretation of the DAMA/LIBRA signal with the Super-Kamiokande experiment. The DAMA/LIBRA signal favors dark matter with low mass and high scattering cross section. We show that these characteristics imply that the scattering cross section that enters the DAMA/LIBRA event rate determines the annihilation rate probed by Super-Kamiokande. Current limits from Super-Kamiokande through-going events do not test the DAMA/LIBRA favored region. We show, however, that upcoming analyses including fully-contained events with sensitivity to dark matter masses from 5 to 10 GeV may corroborate the DAMA/LIBRA signal. We conclude by considering three specific dark matter candidates, neutralinos, WIMPless dark matter, and mirror dark matter, which illustrate the various model-dependent assumptions entering our analysis.Comment: 10 pages, 1 figure; v2: projected super-K sensitivity corrected and strengthened, references added; v3: published versio

Parametric modelling of the 3.6um to 8um colour distributions of galaxies in the SWIRE Survey

We fit a parametric model comprising a mixture of multi-dimensional Gaussian functions to the 3.6 to 8um colour and optical photo-z distribution of galaxy populations in the ELAIS-N1 and Lockman Fields of SWIRE. For 16,698 sources in ELAIS-N1 we find our data are best modelled (in the sense of the Bayesian Information Criterion) by the sum of four Gaussian distributions or modes (C_a, C_b, C_c and C_d). We compare the fit of our empirical model with predictions from existing semi-analytic and phenomological models. We infer that our empirical model provides a better description of the mid-infrared colour distribution of the SWIRE survey than these existing models. This colour distribution test is thus a powerful model discriminator and complementary to comparisons of number counts. We use our model to provide a galaxy classification scheme and explore the nature of the galaxies in the different modes of the model. C_a consists of dusty star-forming systems such as ULIRG's. Low redshift late-type spirals are found in C_b, where PAH emission dominates at 8um. C_c consists of dusty starburst systems at intermediate redshifts. Low redshift early-type spirals and ellipticals dominate C_d. We thus find a greater variety of galaxy types than one can with optical photometry alone. Finally we develop a new technique to identify unusual objects, and find a selection of outliers with very red IRAC colours. These objects are not detected in the optical, but have very strong detections in the mid-infrared. These sources are modelled as dust-enshrouded, strongly obscured AGN, where the high mid-infrared emission may either be attributed to dust heated by the AGN or substantial star-formation. These sources have z_ph ~ 2-4, making them incredibly infrared luminous, with a L_IR ~ 10^(12.6-14.1) L_sun.Comment: 44 pages, 10 figures, 6 tables. Accepted for publication in the Astronomical Journa

miR-21 Plays a Dual Role in Tumor Formation and Cytotoxic Response in Breast Tumors

Breast cancer (BrCa) relies on specific microRNAs to drive disease progression. Oncogenic miR-21 is upregulated in many cancers, including BrCa, and is associated with poor survival and treatment resistance. We sought to determine the role of miR-21 in BrCa tumor initiation, progression and treatment response. In a triple-negative BrCa model, radiation exposure increased miR-21 in both primary tumor and metastases. In vitro, miR-21 knockdown decreased survival in all BrCa subtypes in the presence of radiation. The role of miR-21 in BrCa initiation was evaluated by implanting wild-type miR-21 BrCa cells into genetically engineered mouse models where miR-21 was intact, heterozygous or globally ablated. Tumors were unable to grow in the mammary fat pads of miR-21−/− mice, and grew in ~50% of miR-21+/− and 100% in miR-21+/+ mice. The contribution of miR-21 to progression and metastases was tested by crossing miR-21−/− mice with mice that spontaneously develop BrCa. The global ablation of miR-21 significantly decreased the tumorigenesis and metastases of BrCa, while sensitizing tumors to radio-and chemotherapeutic agents via Fas/FasL-dependent apoptosis. Therefore, targeting miR-21 alone or in combination with various radio or cytotoxic therapies may represent novel and efficacious therapeutic modalities for the future treatment of BrCa patients

Ancient homology underlies adaptive mimetic diversity across butterflies

Convergent evolution provides a rare, natural experiment with which to test the predictability of adaptation at the molecular level. Little is known about the molecular basis of convergence over macro-evolutionary timescales. Here we use a combination of positional cloning, population genomic resequencing, association mapping and developmental data to demonstrate that positionally orthologous nucleotide variants in the upstream region of the same gene, WntA, are responsible for parallel mimetic variation in two butterfly lineages that diverged >65 million years ago. Furthermore, characterization of spatial patterns of WntA expression during development suggests that alternative regulatory mechanisms underlie wing pattern variation in each system. Taken together, our results reveal a strikingly predictable molecular basis for phenotypic convergence over deep evolutionary time.We thank the governments of Ecuador, Costa Rica and the United States for permission to collect butterflies. In addition, we thank Larry Gilbert, Durrell Kapan, Ryan Hill, Kenny Kronforst and Nicholas Crawford for their assistance in collecting butterflies. The funding was provided by National Science Foundation awards to S. P. M., M. R. K. and R.D.R. (National Science Foundation