Friedrichsenlindgreen5724

Pevonedistat (MLN4924), a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit (NAE1), has demonstrated significant therapeutic potential in several malignancies. Although multiple mechanisms-of-action have been identified, how MLN4924 induces cell death and its potential as a combinatorial agent with standard-of-care (SoC) chemotherapy in colorectal cancer (CRC) remains largely undefined. In an effort to understand MLN4924-induced cell death in CRC, we identified p53 as an important mediator of the apoptotic response to MLN4924. We also identified roles for the extrinsic (TRAIL-R2/caspase-8) and intrinsic (BAX/BAK) apoptotic pathways in mediating the apoptotic effects of MLN4924 in CRC cells, as well as a role for BID, which modulates a cross-talk between these pathways. Depletion of the anti-apoptotic protein FLIP, which we identify as a novel mediator of resistance to MLN4924, enhanced apoptosis in a p53-, TRAIL-R2/DR5-, and caspase-8-dependent manner. Notably, TRAIL-R2 was involved in potentiating the apoptotic response to MLN4924 in the absence of FLIP, in a ligand-independent manner. Moreoever, when paired with SoC chemotherapies, MLN4924 demonstrated synergy with the irinotecan metabolite SN38. The cell death induced by MLN4924/SN38 combination was dependent on activation of mitochondria through BAX/BAK, but in a p53-independent manner, an important observation given the high frequency of TP53 mutation(s) in advanced CRC. These results uncover mechanisms of cell death induced by MLN4924 and suggest that this second-generation proteostasis-disrupting agent may have its most widespread activity in CRC, in combination with irinotecan-containing treatment regimens.Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

Doxorubicin remains one of the most common causes of cardiotoxicity in patients with lymphoma, leading to significant morbidity and mortality. Early decline in left ventricular (LV) ejection fraction predicts chemotherapy-induced cardiotoxicity and mortality, but limited data exist on doxorubicin-induced subclinical right ventricular (RV) dysfunction. We investigated dose-dependent subclinical doxorubicin-induced RV dysfunction in lymphoma patients.

Thirty-five patients with adult lymphoma treated with doxorubicin were studied. All patients had normal baseline LV ejection fraction (LVEF > 55%), and no known cardiopulmonary disease. We studied the dose-dependent effect of doxorubicin on RV strain by 2D speckle-tracking echocardiography (STE) using a vendor-independent software (TomTec). Images were analyzed offline by two independent observers blinded to the clinical characteristics of the study population. Baseline LVEF, RV fractional area change (RV FAC), RV free wall strain (RV FWS), and RV global lo.5 vs. SP2577 -20.1 ± 2.9,

 = 0.03).

In this cohort of adult lymphoma patients, doxorubicin-based therapy was associated with subclinical RV dysfunction, but not LV dysfunction, at a cumulative dose ≥200 mg m

. Additional studies evaluating the long-term prognostic implications of RV dysfunction in this population are essential.

In this cohort of adult lymphoma patients, doxorubicin-based therapy was associated with subclinical RV dysfunction, but not LV dysfunction, at a cumulative dose ≥200 mg m- 2. Additional studies evaluating the long-term prognostic implications of RV dysfunction in this population are essential.

The present in vitro study investigated if simulated daily use of hydroxyapatite-based gel (15% HAP) remineralizes early caries lesions as effective as weekly use of high fluoride (12,500 ppm) concentration gel, comparing them with artificial saliva alone.

Three tooth blocks were produced from each of 20 bovine teeth. Caries-like lesion was created on each block by 4-day demineralization in acidified gel. The blocks were randomized into three remineralization groups (20 blocks/group); Hydroxyapatite-based gel (Karex gelée, 15% HAP, fluoride-free), fluoride-based gel (Elmex gelée, 12,500 ppm F

), and artificial saliva (AS). Remineralization was conducted using pH-cycling model for 28 days with storage in AS. The pH cycling model consisted of 2 h demineralization once daily for all groups, and 3 min HAP gel application once daily, 3 min fluoride gel application once weekly, or remain in AS only respectively. Baseline and post-test mineral loss were quantified using microradiography.

Paired t-tests (baseline vs.