Pharmacogenomic evaluation of single nucleotide polymorphisms associated with oxaliplatin-induced peripheral neuropathy: a preliminary study

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Pharmacogenomics and analogues of the antitumor agent N6-isopentenyladenosine.

N6-isopentenyladenosine (i6A), a member of the cytokinin family of plant hormones, has potent in vitro antitumour activity in dif- ferent types of human epithelial cancer cell lines. Gene expression profile analysis of i6A-treated cells revealed induction of genes (e.g., PPP1R15A, DNAJB9, DDIT3, and HBP1) involved in the negative regulation of cell cycle progression and reportedly up- regulated during cell cycle arrest in stress conditions. Of 6 i6A analogues synthesized, only the 1 with a saturated double bond of the isopentenyl side chain had in vitro antitumour activity, although weaker than that of i6A, suggesting that i6A biological ac- tivity is highly linked to its structure. In vivo analysis of i6A and the active analogue revealed no significant inhibition of cancer cell growth in mice by either reagent. Thus, although i6A may inhibit cell proliferation by regulating the cell cycle, further studies are needed to identify active analogues potentially useful in vivo

Pharmacokinetics and pharmacogenetics of SSRIs during pregnancy : An observational study

Background: An involvement of selective serotonin reuptake inhibitors (SSRIs) in increasing the risk of malformations, neonatal withdrawal syndrome, has been suggested recently. Here, we aimed to investigate the contribution of individual pharmacogenetics of SSRI on infants' outcome. We also estimated the umbilical/maternal plasma SSRI concentration ratio in the pregnant women still on SSRI therapy at the time of delivery. Methods: Thirty-four pregnant women, referred to our hospital from January 2011 to July 2015, who were given SSRIs in the third trimester, and related children, were considered. The umbilical/maternal plasma SSRI concentration ratio was estimated in 15 mothers still on SSRI therapy at the time of delivery. For patients with pharmacokinetic analyses, blood samples were collected for pharmacogenetic analyses. Results: Nineteen newborns presented clinical signs possibly related to drug toxicity. A high umbilical/maternal plasma ratio of SSRI was observed in 10 of the 15 evaluated newborns. Five mothers were intermediate metabolizers and 1 a poor metabolizer for the major CYP enzyme involved in pharmacokinetic pathway. Conclusions: Individualized psychopharmacologic treatment that takes into account the mother's exposure to SSRI concentrations and eventually her genetic background may become the standard of care to maximize drug benefit and minimize risks to the newborn

Planck pre-launch status: Low Frequency Instrument calibration and expected scientific performance

We give the calibration and scientific performance parameters of the Planck Low Frequency Instrument (LFI) measured during the ground cryogenic test campaign. These parameters characterise the instrument response and constitute our best pre-launch knowledge of the LFI scientific performance. The LFI shows excellent $1/f$ stability and rejection of instrumental systematic effects; measured noise performance shows that LFI is the most sensitive instrument of its kind. The set of measured calibration parameters will be updated during flight operations through the end of the mission.Comment: Accepted for publications in Astronomy and Astrophysics. Astronomy & Astrophysics, 2010 (acceptance date: 12 Jan 2010

The Origin of the Universe as Revealed Through the Polarization of the Cosmic Microwave Background

Modern cosmology has sharpened questions posed for millennia about the origin of our cosmic habitat. The age-old questions have been transformed into two pressing issues primed for attack in the coming decade: How did the Universe begin? and What physical laws govern the Universe at the highest energies? The clearest window onto these questions is the pattern of polarization in the Cosmic Microwave Background (CMB), which is uniquely sensitive to primordial gravity waves. A detection of the special pattern produced by gravity waves would be not only an unprecedented discovery, but also a direct probe of physics at the earliest observable instants of our Universe. Experiments which map CMB polarization over the coming decade will lead us on our first steps towards answering these age-old questions.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 212 author available at http://cmbpol.uchicago.ed

Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%-30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients' homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies' results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer

Observing the Evolution of the Universe

How did the universe evolve? The fine angular scale (l>1000) temperature and polarization anisotropies in the CMB are a Rosetta stone for understanding the evolution of the universe. Through detailed measurements one may address everything from the physics of the birth of the universe to the history of star formation and the process by which galaxies formed. One may in addition track the evolution of the dark energy and discover the net neutrino mass. We are at the dawn of a new era in which hundreds of square degrees of sky can be mapped with arcminute resolution and sensitivities measured in microKelvin. Acquiring these data requires the use of special purpose telescopes such as the Atacama Cosmology Telescope (ACT), located in Chile, and the South Pole Telescope (SPT). These new telescopes are outfitted with a new generation of custom mm-wave kilo-pixel arrays. Additional instruments are in the planning stages.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 177 author available at http://cmbpol.uchicago.ed

Inhibition of StearoylCoA Desaturase Activity Blocks Cell Cycle Progression and Induces Programmed Cell Death in Lung Cancer Cells

Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic lung cancer is ∼5%, hence alternative therapeutic strategies to treat this disease are critically needed. Recent studies suggest that lipid biosynthetic pathways, particularly fatty acid synthesis and desaturation, are promising molecular targets for cancer therapy. We have previously reported that inhibition of stearoylCoA desaturase-1 (SCD1), the enzyme that produces monounsaturated fatty acids (MUFA), impairs lung cancer cell proliferation, survival and invasiveness, and dramatically reduces tumor formation in mice. In this report, we show that inhibition of SCD activity in human lung cancer cells with the small molecule SCD inhibitor CVT-11127 reduced lipid synthesis and impaired proliferation by blocking the progression of cell cycle through the G1/S boundary and by triggering programmed cell death. These alterations resulting from SCD blockade were fully reversed by either oleic (18:1n-9), palmitoleic acid (16:1n-7) or cis-vaccenic acid (18:1n-7) demonstrating that cis-MUFA are key molecules for cancer cell proliferation. Additionally, co-treatment of cells with CVT-11127 and CP-640186, a specific acetylCoA carboxylase (ACC) inhibitor, did not potentiate the growth inhibitory effect of these compounds, suggesting that inhibition of ACC or SCD1 affects a similar target critical for cell proliferation, likely MUFA, the common fatty acid product in the pathway. This hypothesis was further reinforced by the observation that exogenous oleic acid reverses the anti-growth effect of SCD and ACC inhibitors. Finally, exogenous oleic acid restored the globally decreased levels of cell lipids in cells undergoing a blockade of SCD activity, indicating that active lipid synthesis is required for the fatty acid-mediated restoration of proliferation in SCD1-inhibited cells. Altogether, these observations suggest that SCD1 controls cell cycle progression and apoptosis and, consequently, the overall rate of proliferation in cancer cells through MUFA-mediated activation of lipid synthesis

Planck pre-launch status : The Planck-LFI programme

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