Increasing the Proton Intensity of PS and SPS

Recently, a series of meetings were organised with PS and SPS participants, to discuss the possibilities of increasing the proton intensity on the SPS targets (with particular emphasis to CNGS) as well as ISOLDE and nTOF. Increasing the brilliance of the LHC beam, as required for ultimate LHC performance, was also discussed. Several schemes were proposed, as a staged approach, i.e. starting from the most simple and cheap, though difficult, to the more advanced and expensive. After comparing the advantages and disadvantages of the various methods, three basic schemes were retained as candidates for further investigations and as good / necessary starting points for further improvements. Chapter 1 is devoted to PSB and PS issues and contains essentially a description of the three selected schemes. Chapter 2 deals with limitations in the SPS. Chapter 3 is a synthesis of basic conclusions. In the Appendix, a work-plan is presented for PSB and PS theoretical and experimental studies with a time estimate for preliminary results

Acceleration of lead ions in the CERN PS booster and the CERN PS

The new CERN Heavy Ion Accelerating Facility also requires besides a new Linac substantial modifications of existing accelerators. They are imposed by the low speed and the low intensity of the ion beam and, crucially at low energy, by the short lifetime of the partially stripped ions due to charge exchange with the atoms of the residual gas. The upgraded vacuum system hits the limits of a non-bakeable machine and consequently the acceleration had to be sped up by all means. In the Booster this led to injection and RF capture on a fast-rising magnet cycle and a new digital RF beam control system. Beam current transformers had to be replaced by new, heavily shielded ones. Other modifications include a new staircase magnet to distribute ions over the four Booster rings, lengthening of septa and kicker pulses, plus new, bakeable extraction septa and an energy stabilizing RF loop on the flat top in the CPS, and a stripper in the transfer line to the SPS

Conversion of the PS complex as LHC proton pre-injector

CERNs Large Hadron Collider (LHC) [1][2] will be supplied with protons from the injector chain Linac2-PS Booster (PSB)-PS-SPS (Fig. 1). The required transverse beam brilliance (intensity/emittance) is almost twice that of current PS beams and the LHC bunch spacing of 25 ns must be impressed on the beam before its transfer to the SPS. The scheme involves new RF harmonics in the PSB and the PS, an increase of the PSB energy, and two-batch filling of the PS. After a successful test of the main ingredients, a project for converting the PS complex was launched in 1994. Major additions are (i) h=1 RF systems in the PSB, (ii) upgrading of the PSB main magnet supply from 1 to 1.4 GeV operation, (iii) new magnets, septa, power supplies, kicker pulsers for the PSB-PS beam transfer, (iv) 40 and 80 MHz systems in the PS, (v) beam profile measurement devices with improved resolution. A significant part of the effort is being provided by TRIUMF under the Canada-CERN co-operation agreement on the LHC

Requirement for the N-Terminal Coiled-Coil Domain for Expression and Function, but not Subunit Interaction of, the ADPR-Activated TRPM2 Channel

Transient receptor potential melastatin 2 (TRPM2) proteins form multiple-subunit complexes, most likely homotetramers, which operate as Ca2+-permeable, nonselective cation channels activated by intracellular ADP-ribose (ADPR) and oxidative stress. Each TRPM2 channel subunit is predicted to contain two coiled-coil (CC) domains, one in the N-terminus and the other in the C-terminus. Our recent study has shown that the C-terminal CC domain plays an important, but not exclusive, role in the TRPM2 channel assembly. This study aimed to examine the potential role of the N-terminal CC domain. Domain deletion dramatically reduced protein expression and abolished ADPR-evoked currents but did not alter the subunit interaction. Deletion of both CC domains strongly attenuated the subunit interaction, confirming that the C-terminal CC domain is critical in the subunit interaction. Glutamine substitutions into individual hydrophobic residues at positions a and d in the heptad repeats to disrupt the CC formation had no effect on protein expression, subunit interaction, or ADPR-evoked currents. Mutation of Ile658 to glutamine, which did not perturb the CC formation, decreased ADPR-evoked currents without affecting protein expression, subunit interaction, or membrane trafficking. These results collectively suggest the requirement for the N-terminal CC domain for protein expression and function, but not subunit interaction, of the TRPM2 channel

Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma

Id protein family consists of four members namely Id-1 to Id-4. Different from other basic helix–loop–helix transcription factors, they lack the DNA binding domain. Id proteins have been shown to be dysregulated in many different cancer types and their prognostic value has also been demonstrated. Recently, Id-1 has been shown to be upregulated in oesophageal squamous cell carcinoma (ESCC). However, the prognostic implications of Id proteins in ESCC have not been reported. We examined the expression of the Id proteins in ESCC cell lines and clinical ESCC specimens and found that Id protein expressions were dysregulated in both the ESCC cell lines and specimens. By correlating the expression levels of Id proteins and the clinicopathological data of our patient cohort, we found that M1 stage tumours had significantly higher nuclear Id-1 expression (P=0.012) while high nuclear Id-1 expression could predict development of distant metastasis within 1 year of oesophagectomy (P=0.005). In addition, high levels of Id-2 expression in both cytoplasmic and nuclear regions predicted longer patient survival (P=0.041). Multivariate analysis showed that high-level expression of Id-2 in both cytoplasmic and nuclear regions and lower level of nuclear Id-1 expression were independent favourable predictors of survival in our ESCC patients. Our results suggest that Id-1 may promote distant metastasis in ESCC, and both Id-1 and Id-2 may be used for prognostication for ESCC patients

Expression of the inhibitor of DNA-binding (ID)-1 protein as an angiogenic mediator in tumour advancement of uterine cervical cancers

The ID protein, an inhibitor of basic helix-loop-helix (HLH) transcription factors, has been involved in multiple cellular processes. To investigate the association between tumour advancement and ID expressions of uterine cervical cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction and the histoscore with the localisation of ID-1 was determined by immunohistochemistry and patient survival in 60 patients. ID-1 histoscores and mRNA levels both significantly (P<0.05) increased in uterine cervical cancers according to clinical stage regardless of histopathological type or lymph node metastasis. Furthermore, the 36-month survival rate of the 30 patients with high ID-1 was poor (60%), whereas that of the other 30 patients with low ID-1 was significantly higher (83%). ID-1 histoscores and mRNA levels significantly (P<0.0001) correlated with microvessel counts in uterine cervical cancers. Tumour cells show mostly diffuse to strong cytoplasmic expression of ID-1 and also very faint expression in endothelial cells. Moreover, ID-1 expression not only correlated with microvessel counts but also correlated significantly with histoscore. Therefore, ID-1 might work on tumour advancement through angiogenic activity and is considered to be a candidate for a prognostic indicator in uterine cervical cancers

The PS complex produces the nominal LHC beam

The LHC [1] will be supplied, via the SPS, with protons from the pre-injector chain comprising Linac2, PS Booster (PSB) and PS. These accelerators have under-gone a major upgrading programme [2] during the last five years so as to meet the stringent requirements of the LHC. These imply that many high-intensity bunches of small emittance and tight spacing (25 ns) be available at the PS extraction energy (25 GeV). The upgrading project involved an increase of Linac2 current, new RF systems in the PSB and the PS, raising the PSB energy from 1 to 1.4 GeV, two-batch filling of the PS and the installation of high-resolution beam profile measurement devices. With the project entering its final phase and most of the newly installed hardware now being operational, the emphasis switches to producing the nominal LHC beam and tackling the associated beam physics problems. While a beam with transverse characteristics better than nominal has been obtained, the longitudinal density still needs to be increased. An alternative scheme to produce the 25 ns bunch spacing is outlined, together with other promising developments

Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer

INTRODUCTION: Hypoxia-inducible factor (HIF)-1alpha levels in invasive breast carcinoma have been shown to be an adverse prognostic indicator. Cellular HIF-1alpha activity is regulated by factor-inhibiting hypoxia-inducible factor 1 (FIH-1). In hypoxia, FIH-1 hydroxylation of Asn803 within the C-terminal transactivation domain does not occur and HIF-1alpha forms a fully active transcriptional complex. The present study investigates the role of FIH-1 in invasive breast carcinoma and its correlation with hypoxia. METHODS: Microarrayed tissue cores from 295 invasive carcinomas were stained for FIH-1, for HIF-1alpha and for carbonic anhydrase 9. FIH-1 expression was correlated with standard clinicopathological parameters and with the expression of the surrogate hypoxic markers HIF-1alpha and carbonic anhydrase 9. RESULTS: FIH-1 was positive in 239/295 (81%) tumours, 42/295 (14%) exclusively in the nucleus and 54/295 (18%) exclusively in the cytoplasm. Exclusive nuclear FIH-1 expression was significantly inversely associated with tumour grade (P = 0.02) and risk of recurrence (P = 0.04), whereas exclusive cytoplasmic FIH-1 was significantly positively associated with tumour grade (P = 0.004) and carbonic anhydrase 9 expression (P = 0.02). Patients with tumours that excluded FIH-1 from the nucleus had a significantly shorter survival compared with those with exclusive nuclear expression (P = 0.02). Cytoplasmic FIH-1 expression was also an independent poor prognostic factor for disease-free survival. CONCLUSION: FIH-1 is widely expressed in invasive breast carcinoma. As with other HIF regulators, its association between cellular compartmentalization and the hypoxic response and survival suggests that tumour regulation of FIH-1 is an additional important mechanism for HIF pathway activation