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01). After NSBB, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) RA patients, including the 4 fulfilling HRS-AKI criteria. Conclusion Renal perfusion and function depend critically of systolic function and sympathetic hyperactivation in RA. NSBB blunt the sympathetic overdrive on cardiac function, hamper cardiac output, lower RPP below the critical threshold and impair renal function.-blockade should be cautious or even avoided in RA.Background Inclusion of all patients with advanced biliary tract cancer (aBTC), irrespective of anatomic location, in prospective trials, is debated. Survival rates from landmark analysis offer more relevant information once patients have survived for some time. Aim assess survival impact of BTC anatomic site origin and landmark survival (LS). Patients and methods Patients enrolled into prospective first-line aBTC clinical trials were included. OS was analysed using Cox-proportional-hazard-regression; LS and 95% confidence intervals (CIs) were calculated. Results Overall 1333 patients included (Jan 97-Dec 15); median age 63-years (range 23-85); 46%-male; 84%-ECOG-PS0/1; 25%-locally-advanced (LA), 72%-metastatic, 3%-not reported (NR); gallbladder-(GBC) 385 (29%), cholangiocarcinoma not-specified-(CCA-NS) 363 (27%), extrahepatic-(EHC) 247 (19%), intrahepatic-(IHC) 209 (16%), ampulla 53 (4%), 76 (6%) NR. Treatment was mono-chemotherapy 310-(23%), cisplatin/gemcitabine 482-(36%), other combination 520-(39%), NR 21-(2%). Median OS 10.2-months (95%-CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs GBC EHC-(P.05, P=.08 respectively). Conclusions Patients with GBC have worse OS compared to other anatomic BTC sites; should be considered as a stratification factor in clinical trials. LS rates allow adjusted prognosis prediction for aBTC survivors.Neuroactive steroid 20-oxo-5β-pregnan-3α-yl L-glutamyl 1-ester (PA-Glu), a synthetic analogue of naturally occurring 20-oxo-5β-pregnan-3α-yl sulfate (pregnanolone sulfate, PA-S), inhibits N-methyl-D-aspartate (NMDA) receptors and possesses neuroprotective properties and minimal adverse effects. Herein, we report in vivo effects of new structural modifications of the PA-S molecule a nonpolar modification of the steroid D-ring (5β-androstan-3α-yl L-glutamyl 1-ester, AND-Glu), attachment of a positively charged group to C3 (20-oxo-5β-pregnan-3α-yl L-argininate dihydrochloride salt, PA-Arg) and their combination (5β-androstan-3α-yl L-argininate dihydrochloride salt, AND-Arg). The first aim of this study was to determine the structure-activity relationship for neuroprotective effects in a model of excitotoxic hippocampal damage in rats, based on its behavioral correlate in Carousel maze. The second aim was to explore side effects of neuroprotective steroids on motor functions, anxiety (elevated plus maze) and locomotor activity (open field) and the effect of their high doses in mice. The neuroprotective properties of PA-Glu and AND-Glu were proven, with the effect of the latter appearing to be more pronounced. In contrast, neuroprotective efficacy failed when positively charged molecules (PA-Arg, AND-Arg) were used. AND-Glu and PA-Glu at the neuroprotective dose (1 mg/kg) did not unfavorably influence motor functions of intact mice. Moreover, anxiolytic effects of AND-Glu and PA-Glu were ascertained. These findings corroborate the value of research of steroidal inhibitors of NMDA receptors as potential neuroprotectants with slight anxiolytic effect and devoid of behavioral adverse effects. Taken together, the results suggest the benefit of the nonpolar D-ring modification, but not of the attachment of a positively charged group to C3.In the recent years, coumarin bioactive compounds have been identified to posess anticancer properties. Therefore, the aim of the present study was to investigate for the first time the efficacy of osthole, umbelliferone, esculin, and 4-hydroxycoumarin, alone and in combination with Temozolomide, in the elimination of deadly brain tumors, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) cells via programmed death. Our results indicated that osthole, umbelliferone, esculin, and 4-hydroxycoumarin initiated mainly apoptosis in the T98G and MOGGCCM cells. 1400W Osthole was the most effective. It also initiated autophagy in a small percentage of the cell population. The co-incubation with Temozolomide did not increase the pro-apoptotic potential of natural compounds but decreased the level of autophagy in the T98G cells. Apoptosis was associated with reduced mitochondrial membrane potential, activation of caspase 3, inhibition of Bcl-2 expression and the presence of a Bcl-2/Beclin 1. Blocking of Bcl-2 expression resulted in promotion of apoptosis, but not autophagy, in the MOGGCCM and T98G lines. It also sensitized astrocytoma cells, but not GBM, to the combined osthole and TMZ treatment, which was correlated with a reduced level of Beclin 1 and increased expression of caspase 3. Osthole and TMZ, alone and in combination, inhibited the migratory phenotype of the GBM and AA cells. In summary, our results indicated that osthole effectively eliminated glioma cells via apoptosis, what was correlated with Bcl-2/Beclin 1 complex formation. Considering the anti-migratory effect, osthole and Temozolomide display antiglioma potential but it needs further extensive studies.Soluble guanylyl cyclase (sGC), the major receptor for nitric oxide (NO), is a heterodimer consisting of two subunits, the α and the β subunit. The NO/sGC/cGMP signaling pathway is protective in different disease pathomechanisms including angina pectoris, pulmonary hypertension and fibrotic diseases. The natural ligand heme has two carboxylic acids which interact in the β1 heme nitric oxide oxygen binding (HNOX) domain with the amino acids of the highly conserved Y-x-S-x-R motif. The Y-x-S-x-R motif is also involved in binding of the dicarboxylic activators cinaciguat and BAY 60-2770 as indicated by crystallization studies of sGC activator and bacterial HNOX homologs. To what extent the Y-x-S-x-R motif hydrogen bond network contributes to binding of monocarboxylic acids has not been examined so far. In the current paper, the chemical structural formula of the novel monocarboxylic drug BAY-543 is described for the first time. Using this novel drug, we evaluate the importance of the amino acids Y135 and R139 for thermostabilization and activation in comparison to the dicarboxylic acid BAY 60-2770.