Novel Nitro-Heteroaromatic Antimicrobial Agents for the Control and Eradication of Biofilm-Forming Bacteria

The synthesis and biological activity of several novel nitrothiazole, nitrobenzothiazole, and nitrofuran containing antimicrobial agents for the eradication of biofilm-forming Gram-negative and Gram-positive pathogens is described. Nitazoxanide (NTZ), nitrofurantoin, and furazolidone are commercial antimicrobials which were used as models to show how structural modification improved activity toward planktonic bacteria via minimum inhibitory concentration (MIC) assays and biofilms via minimum biofilm eradication concentration (MBEC) assays. Structure–activity relationship (SAR) studies illustrate the ways in which improvements have been made to the aforementioned antimicrobial agents. It is of particular interest in this regard that the introduction of a chloro substituent at the 5-position of NTZ (analog 1b) resulted in marked activity enhancement, as did the replacement of the 2-acetoxy substituent in the latter compound with a basic amine group (analog 7b). It is also of importance that analog 4a, which is a simple methacrylamide, displayed noteworthy activity against S. epidermidis biofilms. These lead compounds identified to have high activity towards biofilms provide promise as starting points in future pro-drug studies.

La respuesta de la política fiscal a la actividad económica en los países desarrollados

This paper studies how discretional fiscal policy has reacted to economic fluctuations in a group of OCDE countries during the last four decades. Following the recent literature, we use the cyclically adjusted primary balance as a tool to identify government fiscal activity. The results suggest a limited use of fiscal policy in expansion or recession circumstances just as a marked activity in economic stability situations. The reasons behind this performance barely conventional will be examined; we analyze the different responses of taxes and expenditures, pay attention to the importance of fiscal policy at the beginning and evaluate the monetary policy accommodation.

THE REPRESSIVE POLICY OF THE POLISH AUTHORITIES AGAINST THE GREEK CATHOLIC CLERGY 1919–1921

In the scientific article, the author reveals the attitude of Polish government structures to the Ukrainian Greek Catholic clergy in Galicia in 1919–1921. The author defines the nature of repressions against priests in this region. On June 22, 1919 many Greek Catholic priests from different parts of Galicia: Anatol Dolyńskii, Ivan Halibei, Mykola Nyklych and others were taken to Lviv prison “Bridgits” without any guilt. Some of the priests founded themselves in a camp for prisoners at Stshalkovo near Poznan. The higher clergy also suffered persecution. In November 1918, in connection with the “separation in political life”, a search was carried out at the premises of the Przemysl bishop Josaphat Kotsylovsky. The polish officer, Karminski, behaved unce- remoniously with the Ukrainian lord Yo. Kotsylovskyi. The scientific article also notes that the Greek Catholic clergy showed marked activity during the census of the population in September 1921. The general population census of 1921 turned into a peculiar anti- occupational plebiscite.

Induction of Activity Synchronization among Primed Hippocampal Neurons out of Random Dynamics is Key for Trace Memory Formation and Retrieval

Memory is thought to be encoded by sparsely distributed neuronal ensembles in memory-related regions. However, it is unclear how memory-eligible neurons react incrementally during learning to encode trace fear memory, and how they respond to cues to retrieve the memory. We implemented fiber-optic confocal fluorescence endoscopy to directly visualize calcium dynamics of hippocampal CA1 neurons in freely behaving mice, which were subjected to trace fear conditioning. Here we report that the overall activity levels of CA1 principal neurons showed a right-skewed lognormal-like distribution. A small portion of highly active neurons (termed Primed Neurons) exhibited high sensitivity to sensory stimuli and marked activity plasticity. The Primed Neurons maintained random activity status for at least 5 hours in multiple contexts, including those prior to training and prior to recall. Repetitive training induced Primed Neurons to shift from random activity to a well-tuned synchronization. Importantly, the emergence of activity synchronization coincided with the appearance of mouse freezing behaviors. In recall, a partial synchronization among the same population of Primed Neurons was induced from originally random activity, which also coincided with mouse freezing behaviors. Additionally, training-induced synchronization facilitated robust calcium entry into individual Primed Neurons. In contrast, most CA1 neurons stayed silent and did not respond significantly to tone and foot-shock throughout the training and recall testing cycles. In conclusion, highly active Primed Neurons are preferably recruited to encode trace fear memory, and induction of activity synchronization among Primed Neurons out of random dynamics is critical for trace memory formation and memory retrieval.Significance StatementThe overall activity levels of hippocampal principal CA1 neurons show a right-skewed lognormal-like distribution.A small portion of CA1 neurons (termed Primed Neurons) exhibit high activity and marked activity plasticity during learning and recall.Primed Neurons in the hippocampus are preferably recruited to encode trace fear memory, whereas the majority of CA1 neurons show little activity and little activity change during fear conditioning and recall testing.Induction of activity synchronization among Primed Neurons out of random dynamics is critical for trace memory formation and memory retrieval.Training-induced synchronization drastically increases calcium entry into Primed Neurons, which may promote memory consolidation.

Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study

The authors report a phase 1 study of romidepsin combined with oral 5-azacytidine in patients with relapsed/refractory lymphomas, including complete remissions in 3 patients with angioimmunoblastic T-cell lymphoma.

Effect of epigenetic modifier-based combinations on efficacy in patients with peripheral T-cell lymphoma (PTCL): Deciphering impact of mutations in epigenetic operations on response.

7565 Background: Recurring mutations in epigenetic functions in PTCL, coupled with marked activity of epigenetic drugs, raises a question regarding whether these mutations might portend greater vulnerability to one drug over another. For example, do mutations in genes governing DNA methylation suggest these patients might benefit from a hypomethylating (HMA) agent? Preclinical data from our group suggests marked synergism between histone deacetylase inhibitors (HDACi) and HMA, as well as HDACi and pralatrexate (PDX), irrespective of mutations in epigenetic genes. Phase 1 studies (romidepsin [R] plus PDX or R plus 5-azacytidine [Aza]) are completed, and the Phase 2 studies are near completion. This clinical trial scenario affords a unique opportunity to decipher the impact of a HMA on response as a function of TET2, IDH2, DNMT3 and other mutations in PTCL. Methods: Patients with R/R lymphoma were eligible for the phase 1, whereas the phase 2 only enrolled patients with PTCL, either R/R or treatment-naïve individuals. Exploratory endpoints included next generation sequencing (NGS) and methylation arrays. Results: In toto, 89 patients have been enrolled on both trials across all histology’s, 58 have PTCL. NGS and efficacy data is available for the majority of patients, with some from the PDX + R study in process. The ORR among the PTCL patients for PDX+R and Aza+R has been 71% and 73% respectively. Eight of 9 angioimmunoblastic TCL patients responded. Among those with TET2 mutations, 7 of 8 responded to the Aza based treatment, while only 3 of 6 (50%) who were TET2 negative responded. Similarly, of 3 patients with DNMT3 treated with Aza based therapy, all 3 responded. Remarkably one patient with a TET2 mutation experienced progression to PDX+R, and CR to Aza+R. Among the PTCL patients treated with Aza, the global demethylation score (GDMS) demonstrated marked demethylation among all patients, with no correlation between the score and likelihood of response. Conclusions: We will share the completely annotated analysis correlating clinical metrics to the spectrum of epigenetic mutations and GDMS and across all histology’s and treatments. Clinical trial information: NCT01998035; NCT01947140.

Antibacterial Activity of Antibiotic-Impregnated Bone Cement Based Coatings Against Microorganisms with Different Antibiotic Resistance Levels

Purpose — to evaluate the presence and duration of antibiotic activity of antibiotic-impregnated bone cement based coatings samples against antibiotic-sensitive and antibiotic-resistant microorganisms.Material and Methods. Bone cement based coatings impregnated with antibiotics (gentamycin, vancomycin, colistin, meropenem, fosfomycin) are formed on titanium (Ti) plates. A plate rinse was carried out; antibiotic concentrations in the rinsed solutions were estimated by a serial broth microdilution method. Antibacterial activity of the control and rinsed samples against the antibiotic-sensitive and multiple-antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa strains was estimated by a bilayer agar method.Results. The meropenem and fosfomycin concentrations in the rinsed solutions obtained at a one-fold (16 μg/ml for both antibiotics) and two-fold treatment (2 μg/ml for meropenem and 8 μg/ml for fosfomycin) were sufficient to suppress the growth of the control strains. One-fold rinse of samples with colistin eliminated their antibacterial activity completely. The marked activity of the samples with meropenem and fosfomycin persisted against the antibiotic-sensitive P. aeruginosa ATCC 27853 strain after 2 rinse cycles; single-rinsed samples with fosfomycin also maintained the activity against the extensively antibioticresistant P. aeruginosa BP-150 strain. Vancomycin-containing samples possessed the sufficient antibacterial activity against both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) S. aureus strains; two-fold rinse of the samples eliminated their bactericidal properties.Conclusion. Bone cement based coatings impregnated with fosfomycin and meropenem possess the most marked and long-lasting antibacterial activity, manifested mainly against the antibiotic-sensitive strains.

A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma

Key Points The combination of romidepsin and pralatrexate is safe and well tolerated in patients with relapsed/refractory lymphoma. The combination led to an overall response rate of 71% (10/14, with 4/14 complete responses) in patients with relapsed/refractory T-cell lymphoma.