De Novo

The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state 1H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

A protocol for the ab initio crystal structure determination of powdered solids at natural isotopic abundance by combining solid-state NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations was evaluated to determine the crystal structures of four small drug molecules: cocaine, flutamide, flufenamic acid, and theophylline. For cocaine, flutamide and flufenamic acid, we find that the assigned 1H isotropic chemical shifts provide sufficient discrimination to determine the correct structures from a set of predicted structures using the root-mean-square deviation (rmsd) between experimentally determined and calculated chemical shifts. In most cases unassigned shifts could not be used to determine the structures. This method requires no prior knowledge of the crystal structure, and was used to determine the correct crystal structure to within an atomic rmsd of less than 0.12 Å with respect to the known reference structure. For theophylline, the NMR spectra are too simple to allow for unambiguous structure selection

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND: Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS: This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS: From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7.0 years (IQR 5.2-8.7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0.54, 95% CI 0.4-0.73, p<0.0001), with 5-year progression-free survival of 47.6% (95% CI 38.8-55.9) in the immediate treatment group and 31.8% (24.2-39.6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION: Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING: Lilly, Canadian Cancer Society Research

The low-frequency radio telescope NenuFAR

International audienceNenuFAR is a new, large low-frequency radio telescope, in construction and commissioning at the Nançay Radioastronomy Observatory, that starts to provide high sensitivity observations in the 10-85 MHz range. NenuFAR’s 1938 dual polarization antennas are connected to a suite of receivers allowing the instrument to operate, simultaneously if needed, in 4 distinct modes : as a standalone beamformer, a standalone imager, a waveform snapshots recorder, and a giant low-frequency station of the LOFAR array. We provide here an overview of the antennas, receivers, data products, operation and scientific context of the instrument

The low-frequency radio telescope NenuFAR

International audienceNenuFAR is a new, large low-frequency radio telescope, in construction and commissioning at the Nançay Radioastronomy Observatory, that starts to provide high sensitivity observations in the 10-85 MHz range. NenuFAR’s 1938 dual polarization antennas are connected to a suite of receivers allowing the instrument to operate, simultaneously if needed, in 4 distinct modes : as a standalone beamformer, a standalone imager, a waveform snapshots recorder, and a giant low-frequency station of the LOFAR array. We provide here an overview of the antennas, receivers, data products, operation and scientific context of the instrument

The low-frequency radio telescope NenuFAR

International audienceNenuFAR is a new, large low-frequency radio telescope, in construction and commissioning at the Nançay Radioastronomy Observatory, that starts to provide high sensitivity observations in the 10-85 MHz range. NenuFAR’s 1938 dual polarization antennas are connected to a suite of receivers allowing the instrument to operate, simultaneously if needed, in 4 distinct modes : as a standalone beamformer, a standalone imager, a waveform snapshots recorder, and a giant low-frequency station of the LOFAR array. We provide here an overview of the antennas, receivers, data products, operation and scientific context of the instrument

The low-frequency radio telescope NenuFAR

International audienceNenuFAR is a new, large low-frequency radio telescope, in construction and commissioning at the Nançay Radioastronomy Observatory, that starts to provide high sensitivity observations in the 10-85 MHz range. NenuFAR’s 1938 dual polarization antennas are connected to a suite of receivers allowing the instrument to operate, simultaneously if needed, in 4 distinct modes : as a standalone beamformer, a standalone imager, a waveform snapshots recorder, and a giant low-frequency station of the LOFAR array. We provide here an overview of the antennas, receivers, data products, operation and scientific context of the instrument