Parametric fitting of data obtained from detectors with finite resolution and limited acceptance

A goodness-of-fit test for the fitting of a parametric model to data obtained from a detector with finite resolution and limited acceptance is proposed. The parameters of the model are found by minimization of a statistic that is used for comparing experimental data and simulated reconstructed data. Numerical examples are presented to illustrate and validate the fitting procedure.Comment: 11 pages, two figure

Determinants of Functionality in the Ubiquitin Conjugating Enzyme Family

AbstractThe E2 enzymes are key enzymes in the ubiquitin and ubiquitin-like protein ligation pathways. To understand the functionality of the different E2 enzymes, we analyzed 190 protein sequences and 211 structures and electrostatic potentials. Key findings include: The ScUbc1 orthologs are defined by a C-terminal UBA domain. An N-terminal sequence motif that is highly conserved in all E2s except for Cdc34 orthologs is important for the stabilization of the L7 loop and is likely to be involved in E1 binding. ScUbc11p has a different electrostatic potential from E2-Cp and other proteins with which it has high sequence similarity but different functionality. All the E2s known to ubiquitinate histones have a negative potential. The members of the NCUBE family have a positive electrostatic potential, although its form is different from that of the SUMO conjugating E2s. The specificities of only the ScUbc4/Ubc5 and ScUbc1p orthologs are reflected in their L4 and L7 loops

Anisotropic low field behavior and the observation of flux jumps in CeCoIn5

The magnetic behavior of the heavy fermion superconductor CeCoIn5 has been investigated. The low field magnetization data show flux jumps in the mixed state of the superconducting phase in a restricted range of temperature. These flux jumps begin to disappear below 1.7 K, and are completely absent at 1.5 K. The magnetization loops are asymmetric, suggesting that surface and geometrical factors dominate the pinning in this system. The lower critical field (Hc1), obtained from the magnetization data, shows a linear temperature dependence and is anisotropic. The calculated penetration depth is also anisotropic, which is consistent with the observation of an anisotropic superconducting gap in CeCoIn5. The critical currents, determined from the high field isothermal magnetization loops, are comparatively low (around 4000 A/cm2 at 1.6 K and 5 kOe).Comment: 4 pages 3 figure

Real time response on dS_3: the Topological AdS Black Hole and the Bubble

We study real time correlators in strongly coupled N=4 supersymmetric Yang-Mills theory on dS_3 x S^1, with antiperiodic boundary conditions for fermions on the circle. When the circle radius is larger than a critical value, the dual geometry is the so-called "topological AdS_5 black hole". Applying the Son- Starinets recipe in this background we compute retarded glueball propagators which exhibit an infinite set of poles yielding the quasinormal frequencies of the topological black hole. The imaginary parts of the propagators exhibit thermal effects associated with the Gibbons-Hawking temperature due to the cosmological horizon of the de Sitter boundary. We also obtain R-current correlators and find that after accounting for a small subtlety, the Son-Starinets prescription yields the retarded Green's functions. The correlators do not display diffusive behaviour at late times. Below the critical value of the circle radius, the topological black hole decays to the AdS_5 "bubble of nothing". Using a high frequency WKB approximation, we show that glueball correlators in this phase exhibit poles on the real axis. The tunnelling from the black hole to the bubble is interpreted as a hadronization transition.Comment: 52 pages, 11 figures, typos corrected, references adde

Cabazitaxel versus docetaxel for treatment of metastatic castrate refractory prostate cancer

Objectives To assess cabazitaxel versus docetaxel re-challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy. Patients and Methods The CANTATA trial was a prospective, two-arm, open-label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0–2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression-free survival (PFS) as defined by either date of pain progression, date of a cancer-related skeletal-related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012-003835-40 Results Between 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54–76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported. Conclusion Due to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy

Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy

Purpose Impaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE). Method In 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation. Results While post-synaptic GABAB-mediated inhibition was unchanged in IGE (p = 0.09), LICF was reduced compared to controls (controls: 141 ± 17% of baseline; untreated patients: 107 ± 12%, p = 0.2; treated patients: 79 ± 10%, p = 0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56 ± 4% of baseline vs. 26 ± 6% in controls, p = 0.004) and normalised with treatment (37 ± 12%, p = 0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120 ± 10% of baseline, p = 0.017), but not in treated patients. Conclusion Pre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis

Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both

Importance Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. Objective To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. Design, Setting, and Participants The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. Interventions Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. Main Outcomes and Measures Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression–free interval, total SREs, and overall survival (OS). Results Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91). Conclusions and Relevance Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy