Characterizing the critical role of metabolic and redox homeostasis in colorectal cancer

Metabolic alterations are a hallmark of cancer and the mechanism by which these adaptations sustain cancer cell growth are complex and dependent on tissue type. In colon cancer, Peroxisome Proliferator Activated Receptor γ Coactivator 1 β(PGC1��) and Estrogen-Related Receptor α (ERR��) are overexpressed and contribute to tumor growth. Previous studies have shown that PGC1�� and ERR�� regulate many metabolic processes by controlling vital gene expression. Here, we show that PGC1�� and ERR�� drive oxidative phosphorylation and glycolysis in colon cancer cell lines and we evaluated downstream effectors and processes. A dysfunction in the reductive and oxidative capacity of the cell often aligns with dysfunction in metabolism. Data presented here show that Nrf2, a transcription factor that activates antioxidant response genes, also regulates PGC1�� and ERR��protein expression. Similarly, we also showed K-Ras, a common oncogenic driver in colon cancer, as a regulator of Nrf2 protein expression. However, we determined that the mitochondria following PGC1�� depletion were at optimal polarity compared to the control cells, but not with Nrf2 knockdown, suggesting PGC1�� can function independently of its regulation by Nrf2. These data led to the investigation of downstream effectors of PGC1�� and ERR�� to understand the mechanism by which the metabolic alterations occur. Our data further determined that mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), an essential enzyme at the junction of the TCA cycle and glycolysis, is regulated by both PGC1�� and ERR�� expression. While depletion of PCK2 has a minimal effect on the metabolism and cell viability of immortalized, non-transformed human colon epithelial cells, PCK2 knockdown suppresses oxidative phosphorylation and glycolytic metabolism and decreases cell survival in human colon cancer cells. Elevated concentrations of glucose, but not glutamine, rescue the metabolic effect of PCK2 depletion. PCK2 depletion also leads to a significant buildup in TCA cycle intermediate oxaloacetate, significantly altering flux through malate dehydrogenase correlating with diminished glycolytic and oxidative phosphorylation processes. These findings suggest that the PGC1�� and ERR��-dependent regulation of PCK2 represents a molecular mechanism used by colon cancer cells to maximize metabolic processes and promote cancer growth and survival. Overall, the PGC1�� signaling axis is a vital hub of redox and metabolic regulation to enhance cancer cell health, which is not present in normal cells

Selected Topics in High Energy Semi-Exclusive Electro-Nuclear Reactions

We review the present status of the theory of high energy reactions with semi-exclusive nucleon electro-production from nuclear targets. We demonstrate how the increase of transferred energies in these reactions opens a complete new window in studying the microscopic nuclear structure at small distances. The simplifications in theoretical descriptions associated with the increase of the energies are discussed. The theoretical framework for calculation of high energy nuclear reactions based on the effective Feynman diagram rules is described in details. The result of this approach is the generalized eikonal approximation (GEA), which is reduced to Glauber approximation when nucleon recoil is neglected. The method of GEA is demonstrated in the calculation of high energy electro-disintegration of the deuteron and A=3 targets. Subsequently we generalize the obtained formulae for A>3 nuclei. The relation of GEA to the Glauber theory is analyzed. Then based on the GEA framework we discuss some of the phenomena which can be studied in exclusive reactions, these are: nuclear transparency and short-range correlations in nuclei. We illustrate how light-cone dynamics of high-energy scattering emerge naturally in high energy electro-nuclear reactions.Comment: LaTex file with 51 pages and 23 eps figure

Background free search for neutrinoless double beta decay with GERDA Phase II

The Standard Model of particle physics cannot explain the dominance of matter over anti-matter in our Universe. In many model extensions this is a very natural consequence of neutrinos being their own anti-particles (Majorana particles) which implies that a lepton number violating radioactive decay named neutrinoless double beta ($0\nu\beta\beta$) decay should exist. The detection of this extremely rare hypothetical process requires utmost suppression of any kind of backgrounds. The GERDA collaboration searches for $0\nu\beta\beta$ decay of $^{76}$Ge (^{76}\rm{Ge} \rightarrow\,^{76}\rm{Se} + 2e^-) by operating bare detectors made from germanium with enriched $^{76}$Ge fraction in liquid argon. Here, we report on first data of GERDA Phase II. A background level of $\approx10^{-3}$ cts/(keV$\cdot$kg$\cdot$yr) has been achieved which is the world-best if weighted by the narrow energy-signal region of germanium detectors. Combining Phase I and II data we find no signal and deduce a new lower limit for the half-life of $5.3\cdot10^{25}$ yr at 90 % C.L. Our sensitivity of $4.0\cdot10^{25}$ yr is competitive with the one of experiments with significantly larger isotope mass. GERDA is the first $0\nu\beta\beta$ experiment that will be background-free up to its design exposure. This progress relies on a novel active veto system, the superior germanium detector energy resolution and the improved background recognition of our new detectors. The unique discovery potential of an essentially background-free search for $0\nu\beta\beta$ decay motivates a larger germanium experiment with higher sensitivity.Comment: 14 pages, 9 figures, 1 table; ; data, figures and images available at http://www.mpi-hd.mpg/gerda/publi

Limits on uranium and thorium bulk content in GERDA Phase I detectors

Internal contaminations of $^{238}$U, $^{235}$U and $^{232}$Th in the bulk of high purity germanium detectors are potential backgrounds for experiments searching for neutrinoless double beta decay of $^{76}$Ge. The data from GERDA Phase~I have been analyzed for alpha events from the decay chain of these contaminations by looking for full decay chains and for time correlations between successive decays in the same detector. No candidate events for a full chain have been found. Upper limits on the activities in the range of a few nBq/kg for $^{226}$Ra, $^{227}$Ac and $^{228}$Th, the long-lived daughter nuclides of $^{238}$U, $^{235}$U and $^{232}$Th, respectively, have been derived. With these upper limits a background index in the energy region of interest from $^{226}$Ra and $^{228}$Th contamination is estimated which satisfies the prerequisites of a future ton scale germanium double beta decay experiment.Comment: 2 figures, 7 page

The background in the neutrinoless double beta decay experiment GERDA

The GERmanium Detector Array (GERDA) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double beta decay of 76Ge. The signature of the signal is a monoenergetic peak at 2039 keV, the Q-value of the decay, Q_bb. To avoid bias in the signal search, the present analysis does not consider all those events, that fall in a 40 keV wide region centered around Q_bb. The main parameters needed for the neutrinoless double beta decay analysis are described. A background model was developed to describe the observed energy spectrum. The model contains several contributions, that are expected on the basis of material screening or that are established by the observation of characteristic structures in the energy spectrum. The model predicts a flat energy spectrum for the blinding window around Q_bb with a background index ranging from 17.6 to 23.8*10^{-3} counts/(keV kg yr). A part of the data not considered before has been used to test if the predictions of the background model are consistent. The observed number of events in this energy region is consistent with the background model. The background at Q-bb is dominated by close sources, mainly due to 42K, 214Bi, 228Th, 60Co and alpha emitting isotopes from the 226Ra decay chain. The individual fractions depend on the assumed locations of the contaminants. It is shown, that after removal of the known gamma peaks, the energy spectrum can be fitted in an energy range of 200 kev around Q_bb with a constant background. This gives a background index consistent with the full model and uncertainties of the same size

2νββ2\nu\beta\beta decay of 76^{76}Ge into excited states with GERDA Phase I

Two neutrino double beta decay of $^{76}$Ge to excited states of $^{76}$Se has been studied using data from Phase I of the GERDA experiment. An array composed of up to 14 germanium detectors including detectors that have been isotopically enriched in $^{76}$Ge was deployed in liquid argon. The analysis of various possible transitions to excited final states is based on coincidence events between pairs of detectors where a de-excitation $\gamma$ ray is detected in one detector and the two electrons in the other. No signal has been observed and an event counting profile likelihood analysis has been used to determine Frequentist 90\,\% C.L. bounds for three transitions: ${0^+_{\rm g.s.}-2^+_1}$: $T^{2\nu}_{1/2}>$1.6$\cdot10^{23}$ yr, ${0^+_{\rm g.s.}-0^+_1}$: $T^{2\nu}_{1/2}>$3.7$\cdot10^{23}$ yr and ${0^+_{\rm g.s.}-2^+_2}$: $T^{2\nu}_{1/2}>$2.3$\cdot10^{23}$ yr. These bounds are more than two orders of magnitude larger than those reported previously. Bayesian 90\,\% credibility bounds were extracted and used to exclude several models for the ${0^+_{\rm g.s.}-0^+_1}$ transition

Results on ββ\beta\beta decay with emission of two neutrinos or Majorons in 76^{76}Ge from GERDA Phase I

A search for neutrinoless $\beta\beta$ decay processes accompanied with Majoron emission has been performed using data collected during Phase I of the GERmanium Detector Array (GERDA) experiment at the Laboratori Nazionali del Gran Sasso of INFN (Italy). Processes with spectral indices n = 1, 2, 3, 7 were searched for. No signals were found and lower limits of the order of 10$^{23}$ yr on their half-lives were derived, yielding substantially improved results compared to previous experiments with $^{76}$Ge. A new result for the half-life of the neutrino-accompanied $\beta\beta$ decay of $^{76}$Ge with significantly reduced uncertainties is also given, resulting in $T^{2\nu}_{1/2} = (1.926 \pm 0.095)\cdot10^{21}$ yr.Comment: 3 Figure

Limit on the Radiative Neutrinoless Double Electron Capture of 36^{36}Ar from GERDA Phase I

Neutrinoless double electron capture is a process that, if detected, would give evidence of lepton number violation and the Majorana nature of neutrinos. A search for neutrinoless double electron capture of $^{36}$Ar has been performed with germanium detectors installed in liquid argon using data from Phase I of the GERmanium Detector Array (GERDA) experiment at the Gran Sasso Laboratory of INFN, Italy. No signal was observed and an experimental lower limit on the half-life of the radiative neutrinoless double electron capture of $^{36}$Ar was established: $T_{1/2} >$ 3.6 $\times$ 10$^{21}$ yr at 90 % C.I.Comment: 7 pages, 3 figure

Flux Modulations seen by the Muon Veto of the GERDA Experiment

The GERDA experiment at LNGS of INFN is equipped with an active muon veto. The main part of the system is a water Cherenkov veto with 66~PMTs in the water tank surrounding the GERDA cryostat. The muon flux recorded by this veto shows a seasonal modulation. Two effects have been identified which are caused by secondary muons from the CNGS neutrino beam (2.2 %) and a temperature modulation of the atmosphere (1.4 %). A mean cosmic muon rate of $I^0_{\mu} = (3.477 \pm 0.002_{\textrm{stat}} \pm 0.067_{\textrm{sys}}) \times 10^{-4}$/(s$\cdot$m$^2$) was found in good agreement with other experiments at LNGS at a depth of 3500~meter water equivalent.Comment: 7 pages, 6 figure