Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands

Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-l, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity, The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication

Induction of Colonic Aberrant Crypts in Mice by Feeding Apparent N-Nitroso Compounds Derived From Hot Dogs

Nitrite-preserved meats (e.g., hot dogs) may help cause colon cancer because they contain N-nitroso compounds. We tested whether purified hot-dog-derived total apparent N-nitroso compounds (ANC) could induce colonic aberrant crypts, which are putative precursors of colon cancer. We purified ANC precursors in hot dogs and nitrosated them to produce ANC. In preliminary tests, CF1 mice received 1 or 3 i.p. injections of 5mg azoxymethane (AOM)/kg. In Experiments 1 and 2, female A/J mice received ANC in diet. In Experiment 1, ANC dose initially dropped sharply because the ANC precursors had mostly decomposed but, later in Experiment 1 and throughout Experiment 2, ANC remained at 85 nmol/g diet. Mice were killed after 8 (AOM tests) or 17–34 (ANC tests) wk.Median numbers of aberrant crypts in the distal 2 cm of the colon for 1 and 3 AOMinjections, CF1 controls, ANC (Experiment 1), ANC (Experiment 2),and untreated A/J mice were 31, 74, 12, 20, 12, and 5–6, with P < 0.01 for both ANC tests. Experiment 2 showed somewhat increased numbers of colonic mucin-depleted foci in the ANC-treated group. We conclude that hot-dog-derived ANC induced significant numbers of aberrant crypts in the mouse colon

Challenges for climate change adaptation in Latin America and the Caribbean region

The limited success of international efforts to reduce global warming at levels established in the Paris Agreement, and the increasing frequency and strength of climate impacts, highlight the urgent need of adaptation, particularly in developing countries. Unfortunately, current levels of adaptation initiatives are not enough to counteract the observed impacts and projected risks from climate change in Latin America and the Caribbean (LAC). In this paper, we review and highlight relevant issues that have limited the capacity to transform climate knowledge and parties’ ambitions into action in the region. Current vulnerabilities and climatic impact-drivers in LAC are diverse, complex, and region-specific and their effects are expected to be exacerbated by climate change. However, the advancement of regional and domestic climate agendas has been hindered by scientific gaps, political support, institutional capacity, and financial, technical, human, and economic limitations that are common to many LAC countries. Transforming climate data into multidimensional metrics with useful thresholds for different sectors and understanding their contribution for feasible adaptation strategies are delayed by regional and local conundrums such as lack of inclusive governance, data availability, equity, justice, and transboundary issues. We discuss ways to move forward to develop local and regional climate resilient development actions and a more sustainable future in LAC. The climate science community in LAC needs to strengthen its local, national, and international connections and with decision/policymakers and society to establish a three-way engagement by proposing suitable adaptation actions and international negotiations to reduce the risks and vulnerability associated with climate extremes, climate variability and climate change in the region. The discussions and insights presented in this work could be extrapolated to other countries in the Global South

Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-atrial fibrillation trial.

Objective. We evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF).Background. Predicting long-term maintenance of sinus rhythm in patients with AF is difficult.Methods. Plasma concentrations of three specific cardiac markers [high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT-proBNP) and mid-regional proatrial natriuretic peptide (MR-proANP)] and three stable fragments of vasoactive peptides [mid-regional proadrenomedullin (MR-proADM), copeptin (CT-proAVP) and CT-proendothelin-1 (CT-proET-1)] were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI-AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models.Results. Mean patient age was 68 \ub1 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) [95% confidence intervals (CIs) for 1 SD increment] (1.15 [1.04-1.28], P = 0.007), MR-proANP (1.15 [1.01-1.30], P = 0.04), NT-proBNP (1.24 [1.11-1.39], P = 0.0001) and CT-proET-1 (1.16 [1.01-1.33], P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR-proANP tended to predict subsequent recurrence (adjusted HR [95%CI]) (1.53 [0.98-2.37], P = 0.06).Conclusion. Circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF

Rationale and current perspective for early rhythm control therapy in atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia and an important source for mortality and morbidity on a population level. Despite the clear association between AF and death, stroke, and other cardiovascular events, there is no evidence that rhythm control treatment improves outcome in AF patients. The poor outcome of rhythm control relates to the severity of the atrial substrate for AF not only due to the underlying atrial remodelling process but also due to the poor efficacy and adverse events of the currently available ion-channel antiarrhythmic drugs and ablation techniques. Data suggest, however, an association between sinus rhythm maintenance and improved survival. Hypothetically, sinus rhythm may also lead to a lower risk of stroke and heart failure. The presence of AF, thus, seems one of the modifiable factors associated with death and cardiovascular morbidity in AF patients. Patients with a short history of AF and the underlying heart disease have not been studied before. It is fair to assume that abolishment of AF in these patients is more successful and possibly also safer, which could translate into a prognostic benefit of early rhythm control therapy. Several trials are now investigating whether aggressive early rhythm control therapy can reduce cardiovascular morbidity and mortality and increase maintenance of sinus rhythm. In the present paper we describe the background of these studies and provide some information on their design

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3&nbsp;years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0&nbsp;years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013