Classical mappings of the symplectic model and their application to the theory of large-amplitude collective motion

We study the algebra Sp(n,R) of the symplectic model, in particular for the cases n=1,2,3, in a new way. Starting from the Poisson-bracket realization we derive a set of partial differential equations for the generators as functions of classical canonical variables. We obtain a solution to these equations that represents the classical limit of a boson mapping of the algebra. The relationship to the collective dynamics is formulated as a theorem that associates the mapping with an exact solution of the time-dependent Hartree approximation. This solution determines a decoupled classical symplectic manifold, thus satisfying the criteria that define an exactly solvable model in the theory of large amplitude collective motion. The models thus obtained also provide a test of methods for constructing an approximately decoupled manifold in fully realistic cases. We show that an algorithm developed in one of our earlier works reproduces the main results of the theorem.Comment: 23 pages, LaTeX using REVTeX 3.

SIGNALS FOR MINIMAL SUPERGRAVITY AT THE CERN LARGE HADRON COLLIDER: MULTI-JET PLUS MISSING ENERGY CHANNEL,

We use ISAJET to perform a detailed study of the missing transverse energy \eslt plus multi-jet signal expected from superparticle production at the CERN LHC. Our analysis is performed within the framework of the minimal supergravity model with gauge coupling unification and radiative electroweak symmetry breaking. We delineate the region of parameter space where the \eslt supersymmetry signal should be observable at the LHC and compare it to the regions explorable via searches for sleptons and for chargino/neutralino production. We confirm that, given a data sample of 10~\fb^{-1}, $m_{\tg}\sim 1300$ GeV can be explored if m_{\tq}\gg m_{\tg}, while $m_{\tg}\sim 2000$ GeV can be probed if m_{\tq}\simeq m_{\tg}. We further examine what information can be gleaned from scrutinizing this event sample. For instance, the multi-jet multiplicity yields information on whether squark production makes a significant contribution to the observed \eslt sample. Furthermore, reconstructing hemispheric masses may yield a measure of $m_{\tg}$ to $\sim 15-25\%$. Finally, for favourable ranges of parameters, by reconstructing masses of tagged $b\bar{b}$ jet pairs, it may be possible to detect Higgs bosons produced via sparticle cascade decay chains.Comment: 22 pages (REVTEX); a PS text file (etmiss.ps) and 12 figures (etlhc.uu or etlhc.ps) can be obtained via anonymous ftp at ftp://hep.fsu.edu/anonymous.bae

Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin

Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin. Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS

Anomaly-Free Gauged R-Symmetry

We review the gauging of an R-symmetry in local and global susy. We then construct the first anomaly-free models. We break the R-symmetry and susy at the Planck scale and discuss the low-energy effects. We include a solution to the mu-problem, and the prediction of observable effects at HERA. The models also nicely allow for GUT-scale baryogenesis and R-parity violation without the sphaleron interactions erasing the baryon-asymmetry.Comment: 6 pages, latex, no figures. Talk presented at SUSY-95. Work done in collaboration with A. Chamseddin

Current and novel therapeutic opportunities for systemic therapy in biliary cancer

none24Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.openMarin J.J.G.; Prete M.G.; Lamarca A.; Tavolari S.; Landa-Magdalena A.; Brandi G.; Segatto O.; Vogel A.; Macias R.I.R.; Rodrigues P.M.; Casta A.L.; Mertens J.; Rodrigues C.M.P.; Fernandez-Barrena M.G.; Da Silva Ruivo A.; Marzioni M.; Mentrasti G.; Acedo P.; Munoz-Garrido P.; Cardinale V.; Banales J.M.; Valle J.W.; Bridgewater J.; Braconi C.Marin, J. J. G.; Prete, M. G.; Lamarca, A.; Tavolari, S.; Landa-Magdalena, A.; Brandi, G.; Segatto, O.; Vogel, A.; Macias, R. I. R.; Rodrigues, P. M.; Casta, A. L.; Mertens, J.; Rodrigues, C. M. P.; Fernandez-Barrena, M. G.; Da Silva Ruivo, A.; Marzioni, M.; Mentrasti, G.; Acedo, P.; Munoz-Garrido, P.; Cardinale, V.; Banales, J. M.; Valle, J. W.; Bridgewater, J.; Braconi, C

Loss of Hairless Confers Susceptibility to UVB-Induced Tumorigenesis via Disruption of NF-kappaB Signaling

In order to model squamous cell carcinoma development in vivo, researchers have long preferred hairless mouse models such as SKH-1 mice that have traditionally been classified as ‘wild-type’ mice irrespective of the genetic factors underlying their hairless phenotype. The work presented here shows that mutations in the Hairless (Hr) gene not only result in the hairless phenotype of the SKH-1 and Hr−/− mouse lines but also cause aberrant activation of NFκB and its downstream effectors. We show that in the epidermis, Hr is an early UVB response gene that regulates NFκB activation and thereby controls cellular responses to irradiation. Therefore, when Hr expression is decreased in Hr mutant animals there is a corresponding increase in NFκB activity that is augmented by UVB irradiation. This constitutive activation of NFκB in the Hr mutant epidermis leads to the stimulation a large variety of downstream effectors including the cell cycle regulators cyclin D1 and cyclin E, the anti-apoptosis protein Bcl-2, and the pro-inflammatory protein Cox-2. Therefore, Hr loss results in a state of uncontrolled epidermal proliferation that promotes tumor development, and Hr mutant mice should no longer be considered merely hairless 'wild-type' mice. Instead, Hr is a crucial UVB response gene and its loss creates a permissive environment that potentiates increased tumorigenesis

Corrigendum: Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy.

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P\u2009=\u20097.54E-07; ORGCA\u2009=\u20091.19, ORTAK\u2009=\u20091.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA\u2009=\u20095.52E-04, ORGCA\u2009=\u20091.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus

Tevatron and LEP-II Probes of Minimal and String-Motivated Supergravity Models

We explore the ability of the Tevatron to probe Minimal Supersymmetry with high energy scale boundary conditions motivated by supersymmetry breaking in the context of supergravity/superstring theory. A number of boundary condition possibilities are considered: dilaton-like string boundary conditions applied at the standard GUT unification scale or alternatively at the string scale; and extreme (``no-scale'') minimal supergravity boundary conditions imposed at the GUT scale or string scale. For numerous specific cases within each scenario the sparticle spectra are computed and then fed into ISAJET 7.07 so that explicit signatures can be examined in detail. We find that, for some of the boundary condition choices, large regions of parameter space can be explored via same-sign dilepton and isolated trilepton signals. For other choices, the mass reach of Tevatron collider experiments is much more limited. We also compare mass reach of Tevatron experiments with the corresponding reach at LEP 200.Comment: 44 pages, requires phyzzx.tex, tables.tex, full postscript file including embedded figures available via anonymous ftp at ucdhep.ucdavis.edu as [anonymous.gunion]bgkp.ps, preprint UCD-94-1