Replacing C6F5 groups with Cl and H atoms in frustrated Lewis pairs : H-2 additions and catalytic hydrogenations

2-(Dialkylamino) phenylboranes containing the BXZ group, where X, Z = C6F5, Cl, and H, were prepared in a few synthetic steps and demonstrated the cleavage of H-2 under mild conditions. Depending on the nature of the dialkylamino group, X, and Z, the stability of the produced zwitterionic H-2 adducts varies from isolated solids indefinitely stable in an inert atmosphere to those quickly equilibrating with the initial aminoborane and H-2. Using a combined experimental/computational approach on a series of isostructural aminoboranes (dialkylamino = 2,2,6,6-tetramethylpiperid-1-yl), it was demonstrated that the electro-negativity and the steric effect of the substituents generally follow the trend C6F5 similar to Cl >> H. This observation is useful for designing new FLPs for practical applications. As an example, we demonstrated the hydrogenation of alkynes to cis-alkenes under mild conditions that was catalyzed by a chloro-analogue of the C6F5-substituted aminoborane developed previously. The presence of a BHCl group in the amino-chloroboranes or in their H-2 adducts features facile redistribution of the H and Cl atoms and the formation of polychloro and polyhydrido species.Peer reviewe

Missing Dark Matter in the Local Universe

A sample of 11 thousand galaxies with radial velocities V_ LG < 3500 km/s is used to study the features of the local distribution of luminous (stellar) and dark matter within a sphere of radius of around 50 Mpc around us. The average density of matter in this volume, Omega_m,loc=0.08+-0.02, turns out to be much lower than the global cosmic density Omega_m,glob=0.28+-0.03. We discuss three possible explanations of this paradox: 1) galaxy groups and clusters are surrounded by extended dark halos, the major part of the mass of which is located outside their virial radii; 2) the considered local volume of the Universe is not representative, being situated inside a giant void; and 3) the bulk of matter in the Universe is not related to clusters and groups, but is rather distributed between them in the form of massive dark clumps. Some arguments in favor of the latter assumption are presented. Besides the two well-known inconsistencies of modern cosmological models with the observational data: the problem of missing satellites of normal galaxies and the problem of missing baryons, there arises another one - the issue of missing dark matter.Comment: 19 pages, 7 figures, 1 table (accepted

Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial

BACKGROUND: Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection. METHODS: 651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS). RESULTS: 62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9-15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation. CONCLUSIONS: Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01609543

FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression

Purpose: Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with FGFR1-3 mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with FGFR mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy. Methods: FORT-1 (ClinicalTrials.gov identifier: NCT03410693) was a phase II/III, randomized, open-label trial. Patients with FGFR1/3 mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles; n = 87) or chemotherapy (docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 intravenously once every 3 weeks; n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III; a full interim analysis of phase II was completed. Results: ORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72; P = .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with FGFR3 DNA alterations showed ORRs of 52.4% (11/21; 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15; 95% CI, 7.8 to 55.1) for chemotherapy. Conclusion: To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/3 mRNA overexpression may be better predictors of rogaratinib response

Outcome of uterine sarcoma patients treated with pazopanib: A retrospective analysis based on two European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) clinical trials 62043 and 62072.

Background Uterine sarcomas are a group of mesenchymal tumours comprising several histologies. They have a high recurrence rate following surgery, modest outcome to systemic therapy, and poor overall survival. Pazopanib is a multi-targeted tyrosine kinase inhibitor approved for non-adipocytic advanced soft tissue sarcomas (STS). Here we investigated whether response to pazopanib in patients with uterine sarcomas differs from that of patients with non-uterine sarcomas.Patients and methods Uterine sarcoma patients were retrieved from all soft tissue sarcoma patients treated with pazopanib in EORTC Phase II (n=10) and Phase III (PALETTE) (n=34) studies. Patient and tumour characteristics, response, progression free and overall survival data were compared.Results Forty-four patients with uterine sarcoma were treated with pazopanib. The majority of patients had uterine leiomyosarcoma (LMS) (n=39, 88.6%) with high grade tumours (n=37, 84.1%) compared to 54.8% (n=164) in the non-uterine population. The median age was 55years (range 33-79) and median follow up was 2.3years. Uterine patients were heavily pre-treated, 61.3% having ≥2 lines of chemotherapy prior to pazopanib compared to 40.8% in the non-uterine population. Five patients (11%), all LMS, had a partial response (95% CI 3.8-24.6). Median progression free survival (PFS) 3.0months (95% CI 2.5-4.7) in uterine versus 4.5 (95% CI 3.7-5.1) in non-uterine STS. Median overall survival (OS) was 17.5months (95% CI 11.1-19.6), longer than the non-uterine population, 11.1months (95% CI 10.2-12.0) (p=0.352).Conclusions Despite heavy pre-treatment, pazopanib shows signs of activity in patients with uterine sarcoma with the similar outcomes to patients with non-uterine STS

Państwo i społeczeństwo w XXI wieku : harmonizacja europejskiej przestrzeni współpracy w dziedzinie prawa, kultury i turystyki

Słowo wstępne "Poszerzenie Unii Europejskiej w maju 2004 roku różniło się zasadniczo od wcześniejszych. Wymagało bowiem od państw kandydujących nie tylko ogromnego wysiłku dostosowawczego. Daje się ono porównać raczej z początkowym okresem integracji. Wtedy także trzeba było wkroczyć na zupełnie nieznane ścieżki, które stopniowo doprowadziły do jednolitego systemu instytucjonalnego i prawnego, na którym dziś opiera się Wspólnota. Kraje środkowej części naszego kontynentu wchodziły do Unii również z oczekiwaniem, że członkostwo podniesie rangę tych państw na arenie międzynarodowej oraz jednoznacznie określi ich nową pozycję w Europie. Jednoczenie się Europy jest wyrazem głębokiej wspólnoty kulturowej, czerpiącej ze śródziemnomorskich korzeni naszej cywilizacji."(...

A CMB Gibbs sampler for localized secondary anisotropies

As well as primary fluctuations, CMB temperature maps contain a wealth of additional information in the form of secondary anisotropies. Secondary effects that can be identified with individual objects, such as the thermal and kinetic Sunyaev-Zel'dovich (SZ) effects due to galaxy clusters, are difficult to unambiguously disentangle from foreground contamination and the primary CMB however. We develop a Bayesian formalism for rigorously characterising anisotropies that are localised on the sky, taking the TSZ and KSZ effects as an example. Using a Gibbs sampling scheme, we are able to efficiently sample from the joint posterior distribution for a multi-component model of the sky with many thousands of correlated physical parameters. The posterior can then be exactly marginalised to estimate properties of the secondary anisotropies, fully taking into account degeneracies with the other signals in the CMB map. We show that this method is computationally tractable using a simple implementation based on the existing Commander component separation code, and also discuss how other types of secondary anisotropy can be accommodated within our framework