Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe the main metabolic mechanisms involved in PDAC growth and the biological features that may favor its onset and progression within an immunometabolic context. We also discuss the need to bridge the gap between basic research and clinical practice in order to offer alternative therapeutic approaches for PDAC patients in the more immediate future

Influenza vaccination coverage among medical residents: An Italian multicenter survey

Although influenza vaccination is recognized to be safe and effective, recent studies have confirmed that immunization coverage among health care workers remain generally low, especially among medical residents (MRs). Aim of the present multicenter study was to investigate attitudes and determinants associated with acceptance of influenza vaccination among Italian MRs. A survey was performed in 2012 on MRs attending post-graduate schools of 18 Italian Universities. Each participant was interviewed via an anonymous, self-administered, web-based questionnaire including questions on attitudes regarding influenza vaccination. A total of 2506 MRs were recruited in the survey and 299 (11.9%) of these stated they had accepted influenza vaccination in 2011-2012 season. Vaccinated MRs were older (P = 0.006), working in clinical settings (P = 0.048), and vaccinated in the 2 previous seasons (P < 0.001 in both seasons). Moreover, MRs who had recommended influenza vaccination to their patients were significantly more compliant with influenza vaccination uptake in 2011-2012 season (P < 0.001). "To avoid spreading influenza among patients" was recognized as the main reason for accepting vaccination by less than 15% of vaccinated MRs. Italian MRs seem to have a very low compliance with influenza vaccination and they seem to accept influenza vaccination as a habit that is unrelated to professional and ethical responsibility. Otherwise, residents who refuse vaccination in the previous seasons usually maintain their behaviors. Promoting correct attitudes and good practice in order to improve the influenza immunization rates of MRs could represent a decisive goal for increasing immunization coverage among health care workers of the future. © 2014 Landes Bioscience

HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights

Autophagy is an essential intracellular catabolic mechanism involved in the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism. Its activation enhances cellular tolerance to various stresses and is known to be involved in drug resistance. In cancer, autophagy has a dual role in either promoting or blocking tumorigenesis, and recent studies indicate that epigenetic regulation is involved in its mechanism of action in this context. Specifically, the ubiquitin-binding histone deacetylase (HDAC) enzyme HDAC6 is known to be an important player in modulating autophagy. Epigenetic modulators, such as HDAC inhibitors, mediate this process in different ways and are already undergoing clinical trials. In this review, we describe current knowledge on the role of epigenetic modifications, particularly HDAC-mediated modifications, in controlling autophagy in cancer. We focus on the controversy surrounding their ability to promote or block tumor progression and explore the impact of HDAC6 inhibitors on autophagy modulation in cancer. In light of the fact that targeted drug therapy for cancer patients is attracting ever increasing interest within the research community and in society at large, we discuss the possibility of using HDAC6 inhibitors as adjuvants and/or in combination with conventional treatments to overcome autophagy-related mechanisms of resistance

Design and Synthesis of New Oligopeptidic Parvulin Inhibitors

: Pin1 catalyzes the cis-trans isomerization of pThr-Pro or pSer-Pro amide bonds of different proteins involved in several physio/pathological processes. In this framework, recent research activity is directed towards the identification of new selective Pin1 inhibitors. Here, we developed a set ( 5a - p ) of peptide-based Pin1 inhibitors. Direct-binding experiments allowed the identification of the peptide-based inhibitor 5k as a potent ligand of Pin1. Notably, 5k binds Pin1 with a higher affinity compared to Pin4. The comparative analysis of molecular models of Pin1 and Pin4 with the selected compound, gave a rational explanation of the biochemical activity, and pinpointed the chemical elements that, if opportunely modified, may further improve inhibitory potency, pharmacological properties and selectivity of future peptide-based Parvulin inhibitors. Since 5k showed a limited cell penetration and no antiproliferative activity, it was conjugated to a polyarginine stretch, known to promote cell penetration of peptides, to obtain R8-5k derivative, which displayed an anti-proliferative effect on cancer cell lines compared to non-tumor cells. The effect of R8 on cell proliferation was also investigated. This work doubts the application of the R8 strategy for the development of cell penetrating antiproliferative peptides since it is not inert

Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics

Objective: Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program.Methods: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy. Results: MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen -responsive and-unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells.Conclusions: Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and un-derscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Helium identification with LHCb

International audienceThe identification of helium nuclei at LHCb is achieved using a method based on measurements of ionisation losses in the silicon sensors and timing measurements in the Outer Tracker drift tubes. The background from photon conversions is reduced using the RICH detectors and an isolation requirement. The method is developed using $pp$ collision data at $\sqrt{s}=13\,{\rm TeV}$ recorded by the LHCb experiment in the years 2016 to 2018, corresponding to an integrated luminosity of $5.5\,{\rm fb}^{-1}$. A total of around $10^5$ helium and antihelium candidates are identified with negligible background contamination. The helium identification efficiency is estimated to be approximately $50\%$ with a corresponding background rejection rate of up to $\mathcal O(10^{12})$. These results demonstrate the feasibility of a rich programme of measurements of QCD and astrophysics interest involving light nuclei

Enhanced production of Λb0\Lambda_{b}^{0} baryons in high-multiplicity pppp collisions at s=13\sqrt{s} = 13 TeV

International audienceThe production rate of $\Lambda_{b}^{0}$ baryons relative to $B^{0}$ mesons in $pp$ collisions at a center-of-mass energy $\sqrt{s} = 13$ TeV is measured by the LHCb experiment. The ratio of $\Lambda_{b}^{0}$ to $B^{0}$ production cross-sections shows a significant dependence on both the transverse momentum and the measured charged-particle multiplicity. At low multiplicity, the ratio measured at LHCb is consistent with the value measured in $e^{+}e^{-}$ collisions, and increases by a factor of $\sim2$ with increasing multiplicity. At relatively low transverse momentum, the ratio of $\Lambda_{b}^{0}$ to $B^{0}$ cross-sections is higher than what is measured in $e^{+}e^{-}$ collisions, but converges with the $e^{+}e^{-}$ ratio as the momentum increases. These results imply that the evolution of heavy $b$ quarks into final-state hadrons is influenced by the density of the hadronic environment produced in the collision. Comparisons with a statistical hadronization model and implications for the mechanisms enforcing quark confinement are discussed

Charge-dependent curvature-bias corrections using a pseudomass method

International audienceMomentum measurements for very high momentum charged particles, such as muons from electroweak vector boson decays, are particularly susceptible to charge-dependent curvature biases that arise from misalignments of tracking detectors. Low momentum charged particles used in alignment procedures have limited sensitivity to coherent displacements of such detectors, and therefore are unable to fully constrain these misalignments to the precision necessary for studies of electroweak physics. Additional approaches are therefore required to understand and correct for these effects. In this paper the curvature biases present at the LHCb detector are studied using the pseudomass method in proton-proton collision data recorded at centre of mass energy $\sqrt{s}=13$ TeV during 2016, 2017 and 2018. The biases are determined using $Z\to\mu^+\mu^-$ decays in intervals defined by the data-taking period, magnet polarity and muon direction. Correcting for these biases, which are typically at the $10^{-4}$ GeV$^{-1}$ level, improves the $Z\to\mu^+\mu^-$ mass resolution by roughly 20% and eliminates several pathological trends in the kinematic-dependence of the mean dimuon invariant mass

Search for CP\textit{CP} violation in the phase space of D0→KS0K±π∓D^{0} \rightarrow K_{S}^{0} K^{\pm} \pi^{\mp} decays with the energy test

International audienceA search for $\textit{CP}$ violation in $D^{0} \rightarrow K_{S}^{0} K^{+} \pi^{-}$ and $D^{0} \rightarrow K_{S}^{0} K^{-} \pi^{+}$ decays is reported. The search is performed using an unbinned model-independent method known as the energy test that probes local $\textit{CP}$ violation in the phase space of the decays. The data analysed correspond to an integrated luminosity of $5.4~$fb$^{-1}$ collected in proton-proton collisions by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=13$~TeV, amounting to approximately 950000 and 620000 signal candidates for the $D^{0} \rightarrow K_{S}^{0} K^{-} \pi^{+}$ and $D^{0} \rightarrow K_{S}^{0} K^{+} \pi^{-}$ modes, respectively. The method is validated using $D^{0} \rightarrow K^{-} \pi^{+} \pi^{-} \pi^{+}$ and $D^{0} \rightarrow K_{S}^{0} \pi^{+} \pi^{-}$ decays, where $\textit{CP}$-violating effects are expected to be negligible, and using background-enhanced regions of the signal decays. The results are consistent with $\textit{CP}$ symmetry in both the $D^{0} \rightarrow K_{S}^{0} K^{-} \pi^{+}$ and the $D^{0} \rightarrow K_{S}^{0} K^{+} \pi^{-}$ decays, with $p$-values for the hypothesis of no $\textit{CP}$ violation of 70% and 66%, respectively

Enhanced production of Λb0\Lambda_{b}^{0} baryons in high-multiplicity pppp collisions at s=13\sqrt{s} = 13 TeV

International audienceThe production rate of $\Lambda_{b}^{0}$ baryons relative to $B^{0}$ mesons in $pp$ collisions at a center-of-mass energy $\sqrt{s} = 13$ TeV is measured by the LHCb experiment. The ratio of $\Lambda_{b}^{0}$ to $B^{0}$ production cross-sections shows a significant dependence on both the transverse momentum and the measured charged-particle multiplicity. At low multiplicity, the ratio measured at LHCb is consistent with the value measured in $e^{+}e^{-}$ collisions, and increases by a factor of $\sim2$ with increasing multiplicity. At relatively low transverse momentum, the ratio of $\Lambda_{b}^{0}$ to $B^{0}$ cross-sections is higher than what is measured in $e^{+}e^{-}$ collisions, but converges with the $e^{+}e^{-}$ ratio as the momentum increases. These results imply that the evolution of heavy $b$ quarks into final-state hadrons is influenced by the density of the hadronic environment produced in the collision. Comparisons with a statistical hadronization model and implications for the mechanisms enforcing quark confinement are discussed