A number of genetic interactions are involved in the control of cell cycle, but their role and nature have not been completely clarified. The knowledge of the behavior of these interactions in ...hepatocellular carcinoma, could optimize preventive and therapeutic strategies based on cell cycle restraint. We studied downstream events following c-MYC and CYCLIN D1 gene inhibition, by lipoplex-delivered MYC and CYCLIN D1 antisense oligodeoxy nucleotides (aODNM, aODND1), in in vitro cultured human HepG2 and rat Morris 5123 hepatoma cells. 0.5–20 µM aODNM and aODND1 inhibited in vitro growth of both cell types. Scramble oligomer (SCR) and sense ODNs had no or relatively poor effect. Ten micromolar aODNM and aODND1, but not SCR, also induced a significant increase in the apoptotic index of HepG2 and 5123 cells, and inhibited colony formation in soft agar by HepG2 cells. Treatment of the cells with aODNM plus aODND1 had no additive effect on growth and apoptosis. aODNM and aODND1 induced >50% decrease in c-MYC and CYCLIN D1 gene expression, respectively, at both mRNA and protein level. The inhibition of gene expression by aODNs was highly specific, and SCR was without effect. The reduction in c-MYC and CYCLIN D1 expression by aODNs, was associated with a >50% decrease in E2F1 mRNA and protein production, without changes in CYCLIN A and CYCLIN E expression. These results suggest the involvement of both c-MYC and CYCLIN D1 on E2F1 gene function, and indicate that aODNM and aODND1 may inhibit hepatoma cell growth through down-regulation of the E2F1 gene. The inhibition of E2F1 gene expression by E2F1 aODN, was associated with strong growth restraint of HepG2 cells. Thus, interactions of c-MYC and CYCLIN D1 with E2F1 gene are essential for cell cycle activity in hepatoma cells, and their inhibition may have a therapeutic effect.
The COVID-19 pandemic has challenged researchers and policy makers to identify public safety measures forpreventing the collapse of healthcare systems and reducingdeaths. This narrative review ...summarizes the available evidence on the impact of social distancing measures on the epidemic and discusses the implementation of these measures in Brazil. Articles on the effect of social distancing on COVID-19 were selected from the PubMed, medRXiv and bioRvix databases. Federal and state legislation was analyzed to summarize the strategies implemented in Brazil. Social distancing measures adopted by the population appear effective, particularly when implemented in conjunction with the isolation of cases and quarantining of contacts. Therefore, social distancing measures, and social protection policies to guarantee the sustainability of these measures, should be implemented. To control COVID-19 in Brazil, it is also crucial that epidemiological monitoring is strengthened at all three levels of the Brazilian National Health System (SUS). This includes evaluating and usingsupplementary indicators to monitor the progression of the pandemic and the effect of the control measures, increasing testing capacity, and making disaggregated notificationsand testing resultstransparentand broadly available.
Abstract
Background
Despite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of ...the 90–90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact.
Methods
A scoping review was done following Arksey & O′Malley’s methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles.
Results
Twenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures.
Conclusions
This review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied.
Aim
Evaluating how groups of organisms vary in dispersal capability and how environmental, spatial and temporal signals vary across multiple scales is critical to elucidating metacommunity theory. We ...examined whether the relative contributions of environmental, spatial and hydrological factors have different effects on organismal groups with different dispersal abilities at three spatial scales, and how this knowledge contributes to our understanding of metacommunity dynamics.
Location
Four major Brazilian floodplains, with the largest distance among them of 2,300 Km.
Taxon
10 aquatic organismal groups, ranging from bacterioplankton to fish.
Methods
We sampled lakes connected to the main river in the low‐ and high‐water periods of each floodplain between 2011 and 2012. Different biological groups were analysed across three hierarchical spatial scales (fine, intermediate and subcontinental) within and between floodplain systems. We applied a series of partial redundancy analyses to estimate the relative contributions of environmental factors, spatial factors and hydrological period for each biological group.
Results
At the fine spatial scale, predominantly environmental factors and hydrological period structure metacommunities, although less so for microorganisms than for micro‐invertebrates and macro‐organisms. The relative importance of environmental factors increased at the intermediate spatial scale. At the subcontinental scale, the relative importance of spatial factors increased for all biological groups, but environmental factors remained the primary regulators of microorganisms even at the largest scale.
Main conclusions
This study design allowed us to make more robust inferences about the mechanisms responsible for regulating community structure of distinct biological groups at different spatial scales. Our results suggest that biological groups displaying distinct body size likely determine the spatial extent at which environmental, spatial and hydrological processes prevail as the primary regulators of community structure. These findings are important in guiding the conservation and management of floodplain biodiversity because these systems are naturally highly heterogeneous in space and time.
To perform an external validation and direct comparison of published prognostic models for early prediction of the risk of gestational diabetes mellitus, including predictors applicable in the first ...trimester of pregnancy.
External validation of all published prognostic models in large scale, prospective, multicentre cohort study.
31 independent midwifery practices and six hospitals in the Netherlands.
Women recruited in their first trimester (<14 weeks) of pregnancy between December 2012 and January 2014, at their initial prenatal visit. Women with pre-existing diabetes mellitus of any type were excluded.
Discrimination of the prognostic models was assessed by the C statistic, and calibration assessed by calibration plots.
3723 women were included for analysis, of whom 181 (4.9%) developed gestational diabetes mellitus in pregnancy. 12 prognostic models for the disorder could be validated in the cohort. C statistics ranged from 0.67 to 0.78. Calibration plots showed that eight of the 12 models were well calibrated. The four models with the highest C statistics included almost all of the following predictors: maternal age, maternal body mass index, history of gestational diabetes mellitus, ethnicity, and family history of diabetes. Prognostic models had a similar performance in a subgroup of nulliparous women only. Decision curve analysis showed that the use of these four models always had a positive net benefit.
In this external validation study, most of the published prognostic models for gestational diabetes mellitus show acceptable discrimination and calibration. The four models with the highest discriminative abilities in this study cohort, which also perform well in a subgroup of nulliparous women, are easy models to apply in clinical practice and therefore deserve further evaluation regarding their clinical impact.
Natural polysaccharides have emerged as an important class of bioactive compounds due their beneficial biological effects. Here we investigated the protective and healing effects of ...rhamnogalacturonan (RGal) isolated from Acmella oleracea (L.) R.K. Jansen leaves in an experimental model of intestinal inflammation in mice and in heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2). The findings demonstrated that RGal treatment for 7 days reduced the severity of DSS-induced colitis by protecting mice from weight loss, macroscopic damage and reduction of colon length. When compared to the DSS group, RGal also protected the colon epithelium and promoted the maintenance of mucosal enterocytes and mucus secreting goblet cells, in addition to conserving collagen homeostasis and increasing cell proliferation. In an in vitro barrier function assay, RGal reduced the cellular permeability after exposure to IL-1β, while decreasing IL-8 secretion and claudin-1 expression and preserving the distribution of occludin. Furthermore, we also observed that RGal accelerated the wound healing in Caco-2 epithelial cell line. In conclusion, RGal ameliorates intestinal barrier function in vivo and in vitro and may represent an attractive and promising molecule for the therapeutic management of ulcerative colitis.
Lung cancer is the leading cause of tumor-related death. The lack of effective treatments urges the development of new therapeutic approaches able to selectively kill cancer cells. The connection ...between aberrant microRNA (miRNA - miR) expression and tumor progression suggests a new strategy to fight cancer by interfering with miRNA function. In this regard, LNAs (locked nucleic acids) have proven to be very promising candidates for miRNA neutralization. Here, we employed an LNA-based anti-miR library in a functional screening to identify putative oncogenic miRNAs in non-small-cell lung cancer (NSCLC). By screening NIH-H460 and A549 cells, miR-197 was identified as a new functional oncomiR, whose downregulation induces p53-dependent lung cancer cell apoptosis and impairs the capacity to establish tumor xenografts in immunodeficient mice. We further identified the two BH3-only proteins NOXA and BMF as new miR-197 targets responsible for induction of apoptosis in p53 wild-type cells, delineating miR-197 as a key survival factor in NSCLC. Thus, we propose the inhibition of miR-197 as a novel therapeutic approach against lung cancer.
Background
Despite the well‐known health benefits of physical activity, it is a great challenge to stay physically active for frail–older adults with mobility limitations. The aim of this study was ...to test the (cost‐) effectiveness of a patient‐centred physical therapy strategy (Coach2Move) in which individualized treatment (motivational interviewing, physical examination, individualized goal setting, coaching and advice on self management, and physical training) is combined to increase physical activity level and physical fitness and, thereby, to decrease the level of frailty.
Methods
A randomized controlled trial was performed in 13 physical therapy practices with measurements at 3 and 6 months. Eligible patients were aged 70 years or over and had mobility problems (i.e. difficulties with walking, moving, getting up and changing position from bed or chair to standing, or stair climbing). The primary outcome was physical activity (total and moderate intensity) in minutes per day. Secondary outcomes were as follows: frailty, walking speed and distance, mobility, and quality of life. Data were analysed using linear mixed models for repeated measurements. Healthcare costs and quality‐adjusted life years (QALYs) were computed and combined using net monetary benefit (NMB) for different willingness to pay thresholds. Data on costs, QALYs, and NMBs were analysed using linear mixed models.
Results
One hundred and thirty patients participated in this study. At 6 months, the between‐group difference was significant for moderate‐intensity physical activity in favour of the Coach2Move group mean difference: 17.9 min per day; 95% confidence interval (CI) 4.0 to 34.9; P = 0.012. The between‐group difference for total physical activity was 14.1 min per day (95% CI −6.6 to 34.9; P = 0.182). Frailty decreased more in the Coach2Move group compared with usual care mean difference: −0.03 (95% CI: −0.06 to −0.00; P = 0.027). Compared with usual treatment, the Coach2Move strategy resulted in cost savings (€849.8; 95% CI: 1607 to 90; P = 0.028), an improvement in QALYs, (0.02; 95% CI: 0.00 to 0.03; P = 0.03), and a higher NMB at every willingness to pay threshold.
Conclusions
Older adults with mobility problems are able to safely increase physical activity in their own environment and reduce frailty. This study emphasizes both the potential cost‐effectiveness of a patient‐centred approach in the frail elderly and the importance of physical activity promotion in older adults with mobility limitations.
The prevalence of multidrug-resistant (MDR) bacteria and the limited efficacy of current available antibiotics cause every year approximately 700 000 deaths per year. This study aimed to evaluate the ...anti-inflammatory effect and antibacterial potential of the ibuprofen derivative Methyl 2-(-4-isobutylphenyl)propanoate (MET-IBU). The molecular structure of MET-IBU was confirmed by Nuclear Magnetic Resonance (NMR) and, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) spectroscopy. Our in vivo study using adult zebrafish model demonstrated that the ibuprofen derivative MET-IBU also possesses anti-inflammatory effect, and in vitro antibacterial activity assays showed that in the association of ampicillin, norfloxacin, and gentamicin with MET-IBU occurred reduction in the minimum inhibitory concentration (MIC) for MDR bacterial strains of Escherichia coli 06 and Staphylococcus aureus 10, indicating a potentiating in the growth inhibition of these pathogenic bacteria. Regarding the strain of Staphylococcus aureus K2068 (overexpressing mepA gene), a potentiation of ethidium bromide was found in the association with MET-IBU, indicating the action of this compound on the efflux pump mechanism present in this strains. This result corroborates the molecular docking study that indicated a high affinity of the MET-IBU with the MepA efflux pump. It was also noticed an antibiotic potentiating activity in the association MET-IBU with norfloxacin against strains of Staphylococcus aureus 1199B (overexpressing norA gene) when compared to the norfloxacin control. This enhanced antibiotic effect of MET-IBU is associated with a second resistance mechanism, which is due to the modification in the topoisomerase enzyme. These results bring attention to the ibuprofen derivative MET-IBU as possible candidate for the development of new options for the treatment of bacterial infections with protective anti-inflammatory action.
Display omitted
•Anti-inflammatory and antibacterial evaluation of an ibuprofen derivative.•Antibiotic inhibition mechanisms were evaluated.•Antibiotic potentiation occurs when MET-IBU is associated with antibiotics.•MET-IBU presents anti-inflammatory activity in adult zebrafish model.•MET-IBU possesses inhibitory effect on the MepA efflux pump.
Late-onset sepsis (LOS) is an important cause of morbidity and mortality in very low birth weight (VLBW) infants.
To determine the incidence, risk factors and etiology of LOS.
LOS was investigated in ...a multicenter prospective cohort of infants at eight public university neonatal intensive care units (NICUs). Inclusion criteria included inborn, 23-33 weeks of gestational age, 400-1499 g birth weight, who survived >3 days.
Of 1507 infants, 357 (24%) had proven LOS and 345 (23%) had clinical LOS. Infants with LOS were more likely to die. The majority of infections (76%) were caused by Gram-positive organisms. Independent risk factors for proven LOS were use of central venous catheter and mechanical ventilation, age at the first feeding and number of days on parenteral nutrition and on mechanical ventilation.
LOS incidence and mortality are high in Brazilian VLBW infants. Most risk factors are associated with routine practices at NICU.
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