CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase Inhibition

Androgen deprivation therapy (ADT) is a powerful treatment for metastatic hormone-sensitive prostate cancer (mHSPC) patients, but eventually and inevitably, cancer relapses, progressing to the fatal castration-resistant (CR)PC stage. Progression implies the emergence of cells proliferating in the absence of androgen through still elusive mechanisms. We show here for the first time that ADT induces LNCaP mHSPC cells to collectively enter a metastable quasi-apoptotic state (QUAPS) consisting of partial mitochondrial permeabilization, limited BAX and caspase activation, and moderate induction of caspase-dependent dsDNA breaks; despite this, cells maintain full viability. QUAPS is destabilized by poly(ADP)-polymerase inhibition (PARPi), breaking off toward overt intrinsic apoptosis and culture extinction. Instead, QUAPS is rapidly and efficiently reverted upon androgen restoration, with mitochondria rapidly recovering integrity and cells collectively resuming normal proliferation. Notably, replication restarts before DNA repair is completed, and implies an increased micronuclei frequency, indicating that ADT promotes genetic instability. The recovered cells re-acquire insensitivity to PARPi (as untreated LNCaP), pointing to specific, context-dependent vulnerability of mHSPC cells to PARPi during ADT. Summarizing, QUAPS is an unstable, pro-mutagenic state developing as a pro-survival pathway stabilized by PARP, and constitutes a novel viewpoint explaining how ADT-treated mHSPC may progress to CRPC, indicating possible preventive countermeasures

Apoptosis as Driver of Therapy-Induced Cancer Repopulation and Acquired Cell-Resistance (CRAC): A Simple In Vitro Model of Phoenix Rising in Prostate Cancer

Apoptotic cells stimulate compensatory proliferation through the caspase-3-cPLA-2-COX-2-PGE-2-STAT3 Phoenix Rising pathway as a healing process in normal tissues. Phoenix Rising is however usurped in cancer, potentially nullifying pro-apoptotic therapies. Cytotoxic therapies also promote cancer cell plasticity through epigenetic reprogramming, leading to epithelial-to-mesenchymal-transition (EMT), chemo-resistance and tumor progression. We explored the relationship between such scenarios, setting-up an innovative, straightforward one-pot in vitro model of therapy-induced prostate cancer repopulation. Cancer (castration-resistant PC3 and androgen-sensitive LNCaP), or normal (RWPE-1) prostate cells, are treated with etoposide and left recovering for 18 days. After a robust apoptotic phase, PC3 setup a coordinate tissue-like response, repopulating and acquiring EMT and chemo-resistance; repopulation occurs via Phoenix Rising, being dependent on high PGE-2 levels achieved through caspase-3-promoted signaling; epigenetic inhibitors interrupt Phoenix Rising after PGE-2, preventing repopulation. Instead, RWPE-1 repopulate via Phoenix Rising without reprogramming, EMT or chemo-resistance, indicating that only cancer cells require reprogramming to complete Phoenix Rising. Intriguingly, LNCaP stop Phoenix-Rising after PGE-2, failing repopulating, suggesting that the propensity to engage/complete Phoenix Rising may influence the outcome of pro-apoptotic therapies. Concluding, we established a reliable system where to study prostate cancer repopulation, showing that epigenetic reprogramming assists Phoenix Rising to promote post-therapy cancer repopulation and acquired cell-resistance (CRAC)

Metabolic Reprogramming of Castration-Resistant Prostate Cancer Cells as a Response to Chemotherapy

Prostate cancer at the castration-resistant stage (CRPC) is a leading cause of death among men due to resistance to anticancer treatments, including chemotherapy. We set up an in vitro model of therapy-induced cancer repopulation and acquired cell resistance (CRAC) on etoposide-treated CRPC PC3 cells, witnessing therapy-induced epithelial-to-mesenchymal-transition (EMT) and chemoresistance among repopulating cells. Here, we explore the metabolic changes leading to chemo-induced CRAC, measuring the exchange rates cell/culture medium of 36 metabolites via Nuclear Magnetic Resonance spectroscopy. We studied the evolution of PC3 metabolism throughout recovery from etoposide, encompassing the degenerative, quiescent, and repopulating phases. We found that glycolysis is immediately shut off by etoposide, gradually recovering together with induction of EMT and repopulation. Instead, OXPHOS, already high in untreated PC3, is boosted by etoposide to decline afterward, though stably maintaining values higher than control. Notably, high levels of EMT, crucial in the acquisition of chemoresistance, coincide with a strong acceleration of metabolism, especially in the exchange of principal nutrients and their end products. These results provide novel information on the energy metabolism of cancer cells repopulating from cytotoxic drug treatment, paving the way for uncovering metabolic vulnerabilities to be possibly pharmacologically targeted and providing novel clinical options for CRPC

Construction and test of a full-scale prototype of an ATLAS muon spectrometer tracking chamber

We have built a full scale prototype of the precision tracking chambers (Monitored Drift Tubes, MDT) for the muon spectrometer of the Atlas Experiment at the LHC collider. This article describes in detail the procedures used in constructing the drift tubes and in assembling the chamber. It presents data showing that the required mechanical precision has been achieved as well as test beam results displaying the over all chamber performance. The article presents data demonstrating the derivation of the space-time relation of the drift tubes by the autocalibration procedure using real data from the tracks crossing the chamber. Autocalibration is the procedure which must be used during run time. (C) 1999 Elsevier Science B.V. All rights reserved

Calypso: a full-scale MDT prototype for the ATLAS muon spectrometer

We present a full-scale MDT prototype for the Atlas muon spectrometer. The chamber consists of two multilayers made of three layers of 96 drift tubes each. The main feature of this chamber is the very accurate mechanical construction (20 mu m accuracy on single wire positioning) together with a very good individual tube spatial resolution. In this paper we present results both on the mechanical accuracy of the chamber, and on the performances obtained on the H8 test beam at CERN. In particular, we present an autocalibration method that allows to obtain the space-to-time relation of the tubes with a systematic error less than 20 mu m, the space resolution and the efficiency of the chamber. (C) Published by 1998 Elsevier Science B.V. All rights reserved

Construction of the inner layer barrel drift chambers of the ATLAS muon spectrometer at the LHC

We have designed and built the facilities to assemble the inner layer of the precision tracking chambers (Monitored Drift Tubes, MDT) for the Muon Spectrometer of the ATLAS Experiment at LHC. This article describes in detail the tooling, the procedures and the quality control equipment used in the chambers assembly. Data are presented from the X-ray tomograph at CERN showing that the required chamber mechanical precision has been achieved