CP Violation in the SUSY Seesaw: Leptogenesis and Low Energy

We suppose that the baryon asymmetry is produced by thermal leptogenesis (with flavour effects), at temperatures $\sim 10^{9} - 10^{10}$ GeV, in the supersymmetric seesaw with universal and real soft terms. The parameter space is restricted by assuming that $l_\alpha \to l_\beta \gamma$ processes will be seen in upcoming experiments. We study the sensitivity of the baryon asymmetry to the phases of the lepton mixing matrix, and find that leptogenesis can work for any value of the phases. We also estimate the contribution to the electric dipole moment of the electron, arising from the seesaw, and find that it is (just) beyond the sensitivity of next generation experiments (\lsim 10^{-29} e cm). The fourteen dimensional parameter space is efficiently explored with a Monte Carlo Markov Chain, which concentrates on the regions of interest.Comment: 30 pages, 7 figure

Insensitivity of flavoured leptogenesis to low energy CP violation

If the baryon asymmetry of the Universe is produced by leptogenesis, CP violation is required in the lepton sector. In the seesaw extension of the Standard Model with three hierarchical right-handed neutrinos, we show that the baryon asymmetry is insensitive to the PMNS phases: thermal leptogenesis can work for any value of the observable phases. This result was well-known when there are no flavour effects in leptogenesis; we show that it remains true when flavour effects are included.Comment: 4 pages, 1 figure; version accepted for publication, added explanations, notation clarifie

Radiation dose from multidetector CT studies in children: results from the first Italian nationwide survey

Background Multidetector CT (MDCT) scanners have con- tributed to the widespread use of CT in paediatric imaging. However, concerns are raised for the associated radiation exposure. Very few surveys on radiation exposure from MDCT studies in children are available. Objective The aim of this study was to outline the status of radiation exposure in children from MDCT practice in Italy. Materials and methods In this retrospective multicentre study we asked Italian radiology units with an MDCT scanner with at least 16 slices to provide dosimetric and acquisition param- eters of CT examinations in three age groups (1–5, 6–10, 11– 15 years) for studies of head, chest and abdomen. The dosi- metric results were reported in terms of third-quartile volu- metric CT dose index (CTDIvol) (mGy), size-specific dose estimate (SSDE) (mGy), dose length product (DLP) (mGy cm), and total DLP for multiphase studies. These results were compared with paediatric European and adult Italian published data. A multivariate analysis assessed the association of CTDIvol with patient characteristics and scanning modalities. Results We collected data from 993 MDCT examinations performed at 25 centres. For age groups 1–5 years, 6–10 years and 11–15 years, the CTDIvol, DLP and total DLP values were statistically significantly below the values observed in our analogous national survey in adults, although the difference decreased with increasing age. CTDIvol variability among centres was statistically significant (variance = 0.07; 95% confidence interval = 0.03–0.16; P < 0.001). Conclusions This study reviewed practice in Italian centres performing paediatric imaging with MDCT scanners. The variability of doses among centres suggests that the use of standardised CT protocols should be encourage

Adult exposures from MDCT including multiphase studies: first Italian nationwide survey.

OBJECTIVES: To evaluate the radiation dose in routine multidetector computed tomography (MDCT) examinations in Italian population. METHODS: This was a retrospective multicentre study included 5,668 patients from 65 radiology departments who had undergone common CT protocols: head, chest, abdomen, chest–abdomen–pelvis (CAP), spine and cardiac. Data included patient characteristics, CT parameters, volumetric CT dose index (CTDIvol) and dose length product (DLP) for each CT acquisition phase. Descriptive statistics were calculated, and a multi-regression analysis was used to outline the main factors affecting exposure. RESULTS: The 75th percentiles of CTDIvol (mGy) and DLP (mGy cm) for whole head were 69 mGy and 1,312 mGy cm, respectively; for chest, 15 mGy and 569 mGy cm; spine, 42 mGy and 888 mGy cm; cardiac, 7 mGy and 131 mGy cm for calcium score, and 61 mGy and 1,208 mGy cm for angiographic CT studies. High variability was present in the DLP of abdomen and CAP protocols, where multiphase examinations dominated (71 % and 73 % respectively): for abdomen, 18 mGy, with 555 and 920 mGy cm in abdomen and abdomen–pelvis acquisitions respectively; for CAP, 17 mGy, with 508, 850 and 1,200 mGy cm in abdomen, abdomen–pelvis and CAP acquisitions respectively. CONCLUSION: The results of this survey could help in the definition of updated diagnostic reference levels (DRL)

Dark Matter on the Smallest Scales

This work investigates the dark matters structures that form on the smallest cosmological scales. We find that the types and abundances of structures which form at approximately Earth-mass scales are very sensitive to the nature of dark matter. We explore various candidates for dark matter and determine the corresponding properties of small-scale structure. In particular, we discuss possibilities for indirect detection of dark matter through small-scale structure, and comment on the potential of these methods for discriminating between dark matter candidates.Comment: 10 Pages, Proceedings from the Dark Matter working group at the 86th Les Houches Summer School: Particle Physics and Cosmolog

Glucose starvation induces cell death in K-ras-transformed cells by interfering with the hexosamine biosynthesis pathway and activating the unfolded protein response

Cancer cells, which use more glucose than normal cells and accumulate extracellular lactate even under normoxic conditions (Warburg effect), have been reported to undergo cell death under glucose deprivation, whereas normal cells remain viable. As it may be relevant to exploit the molecular mechanisms underlying this biological response to achieve new cancer therapies, in this paper we sought to identify them by using transcriptome and proteome analysis applied to an established glucoseaddicted cellular model of transformation, namely, murine NIH-3T3 fibroblasts harboring an oncogenic K-RAS gene, compared with parental cells. Noteworthy is that the analyses performed in high-and low-glucose cultures indicate that reduction of glucose availability induces, especially in transformed cells, a significant increase in the expression of several unfolded protein response (UPR) hallmark genes. We show that this response is strictly associated with transformed cell death, given that its attenuation, by reducing protein translation or by increasing cell protein folding capacity, preserves the survival of transformed cells. Such an effect is also observed by inhibiting c-Jun NH2-terminal kinase, a pro-apoptotic signaling mediator set downstream of UPR. Strikingly, addition of N-acetyl-D-glucosamine, a specific substrate for the hexosamine biosynthesis pathway (HBP), to glucose-depleted cells completely prevents transformed cell death, stressing the important role of glucose in HBP fuelling to ensure UPR attenuation and increased cell survival. Interestingly, these results have been fully recognized in a human model of breast cancer, MDA-MB-231 cells. In conclusion, we show that glucose deprivation, leading to harmful accumulation of unfolded proteins in consequence of a reduction of protein glycosylation, induces a UPR-dependent cell death mechanism. These findings may open the way for new therapeutic strategies to specifically kill glycolytic cancer cells

po 259 inhibition of the hexosamine biosynthetic pathway by targeting pgm3 causes breast cancer growth arrest and apoptosis

Introduction Cancer aberrant N - and O -linked protein glycosylation, frequently resulting from an augmented flux through the Hexosamine Biosynthetic Pathway (HBP), play different roles in tumour progression. Recent studies reported an association between the tumorigenic potential, metastasis and chemoresistance of several type of breast cancer cells and tumours, among which the Triple Negative Breast Cancer (TNBC), and the alteration of their membrane glycans composition and ramification as well as of their level of protein O -Glc N Ac. However, the low specificity and toxicity of the existing HBP inhibitors prevented their use for cancer treatment. Material and methods In order to identify a novel inhibitor of HBP pathway and in particular of the PGM3 enzyme, we performed a virtual screening by using computational approaches. These approaches lead us to the identification of a lead compound. This compound, named FR054, has been synthetized and in vitro and in vivo tested by using several biophysical methods (NMR, LC/MS, HPLC) and biochemical assay (CETSA, ITDRF, FACS analysis) as well as tested in TNBC xenograft mice model. Results and discussions Here we report the preclinical evaluation of FR054, a novel inhibitor of the HBP enzyme PGM3, with a remarkable anti-breast cancer effect. In fact, FR054 induces in different breast cancer cells a dramatic decrease in cell proliferation and survival. In particular, in a model of Triple Negative Breast Cancer (TNBC) cells, MDA-MB-231, we show that these effects are correlated to FR054-dependent reduction of both N - and O -glycosylation level that cause also to a strong reduction of cancer cell adhesion and migration. Moreover we show that impaired survival of cancer cells upon FR054 treatment is associated with activation of the Unfolded Protein Response (UPR) and accumulation of intracellular ROS. Finally, we show that FR054 suppresses cancer growth in MDA-MB-231 xenograft mice. Conclusion Our data support the advantage of targeting HBP for therapeutic purpose and encourage further investigation about the use of this small-molecule as promising compound for breast cancer therapy

Energy Metabolism Characterization of a Novel Cancer Stem Cell‐Like Line 3AB‐OS

Cancer stem cells (CSC) have a central role in driving tumor growth. Since metabolism is becoming an important diagnostic and therapeutic target, characterization of CSC line energetic properties is an emerging need. Embryonic and adult stem cells, compared to differentiated cells, exhibit a reduced mitochondrial activity and a stronger dependence on aerobic glycolysis. Here, we aimed to comparatively analyze bioenergetics features of the human osteosarcoma 3AB‐OS CSC‐like line, and the parental osteosarcoma MG63 cells, from which 3AB‐OS cells have been previously selected. Our results suggest that 3AB‐OS cells depend on glycolytic metabolism more strongly than MG63 cells. Indeed, growth in glucose shortage or in presence of galactose or pyruvate (mitochondrial specific substrates) leads to a significant reduction of their proliferation compared to MG63 cells. Accordingly, 3AB‐OS cells show an increased expression of lactate dehydrogenase A (LDHA) and a larger accumulation of lactate in the culture medium. In line with these findings 3AB‐OS cells as compared to MG63 cells present a reduced mitochondrial respiration, a stronger sensitivity to glucose depletion or glycolysis inhibition and a lessened sensitivity to oxidative phosphorylation inhibitors. Additionally, in contrast to MG63 cells, 3AB‐OS display fragmented mitochondria, which become networked as they grow in glucose‐rich medium, while almost entirely loose these structures growing in low glucose. Overall, our findings suggest that 3AB‐OS CSC energy metabolism is more similar to normal stem cells and to cancer cells characterized by a glycolytic anaerobic metabolism