Antimicrobial stewardship in an Internal Medicine ward: effects on antibiotic consumption and on the use of carbapenems.

Assessing the effects of an antimicrobial stewardship program (ASP) implemented in a 78-bed Internal Medicine ward of an Italian mid-sized acute care hospital of 296 beds (26,820 bed days/year in 2015 and 26,653 in 2016). The ASP, implemented in May 2016, included: (a) formulation and dissemination of local guidelines on empiric antibiotic therapy; (b) educational training; and (c) restrictive control on the use of carbapenems. We included in the study all the patients who had received at least one systemic antibiotic as empiric therapy and who were discharged in two comparable time periods (Oct-Nov 2015: period 1 and Oct-Nov 2016: period 2), before and after the implementation of the ASP.

Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors.

A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi).

Mechanisms for concentrating Rho1 during cytokinesis.

The small GTP-binding protein, Rho1/RhoA plays a central role in cytokinetic actomyosin ring (CAR) assembly and cytokinesis. Concentration of Rho proteins at the division site is a general feature of cytokinesis, yet the mechanisms for recruiting Rho to the division site for cytokinesis remain poorly understood. We find that budding yeast utilizes two mechanisms to concentrate Rho1 at the division site.

6-alkylthio-4-[1-(2,6-difluorophenyl)alkyl]-1H-[1,3,5]triazin-2-ones (ADATs): novel regulators of cell differentiation and proliferation.

Novel triazine analogues of 5-alkyl-2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones (F(2)-DABOs), previously described by us as nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs), were tested for their antiproliferative and cytodifferentiating activity on the A-375 human melanoma cell line. Most of the tested derivatives were effective in decreasing cell proliferation, facilitating morphological differentiation, and reprogramming gene expression. All these effects were reversible upon withdrawal of RT inhibitors.

Polo-like kinase Cdc5 controls the local activation of Rho1 to promote cytokinesis.

The links between the cell cycle machinery and the cytoskeletal proteins controlling cytokinesis are poorly understood. The small guanine nucleotide triphosphate (GTP)-binding protein RhoA stimulates type II myosin contractility and formin-dependent assembly of the cytokinetic actin contractile ring. We found that budding yeast Polo-like kinase Cdc5 controls the targeting and activation of Rho1 (RhoA) at the division site via Rho1 guanine nucleotide exchange factors.

6-[1-(2,6-difluorophenyl)ethyl]pyrimidinones antagonize cell proliferation and induce cell differentiation by inhibiting (a nontelomeric) endogenous reverse transcriptase.

Two 2,6-difluoro-DABO derivatives (MC 1047, 1, and MC 1220, 2, respectively) were tested against endogenous, nontelomeric reverse transcriptase (endo-RT) in human differentiating cell systems to investigate their antiproliferative and cytodifferentiating activity. The two compounds significantly reduced cell proliferation and facilitated the morphological differentiation of cells. These results propose F(2)-DABOs as useful tools in preventive and/or curative therapy to counteract the loss of differentiation in dedifferentiating pathologies and as antiproliferative drugs in tumor therapy.