Identification, Expression and Target Gene Analyses of MicroRNAs in Spodoptera litura

MicroRNAs (miRNAs) are small RNAs widely present in animals and plants and involved in post-transcriptional regulation of gene transcripts. In this study we identified and validated 58 miRNAs from an EST dataset of Spodoptera litura based on the computational and experimental analysis of sequence conservation and secondary structure of miRNA by comparing the miRNA sequences in the miRbase. RT-PCR was conducted to examine the expression of these miRNAs and stem-loop RT-PCR assay was performed to examine expression of 11 mature miRNAs (out of the 58 putative miRNA) that showed significant changes in different tissues and stages of the insect development. One hundred twenty eight possible target genes against the 11 miRNAs were predicted by using computational methods. Binding of one miRNA (sli-miR-928b) with the three possible target mRNAs was confirmed by Southern blotting, implying its possible function in regulation of the target genes

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Polyunsaturated fatty acids supplementation impairs anti-oxidant high-density lipoprotein function in heart failure

Background The underlying reasons for the highly inconsistent clinical outcome data for omega3polyunsaturated fatty acids (n3PUFAs) supplementation in patients with cardiac disease have not been understood yet. The aim of this prospective, randomized, doubleblind, placebo controlled study was to determine the effects of oral treatment with n3PUFAs on the antioxidant capacity of HDL in heart failure (HF) patients. Methods A total of 40 patients with advanced HF of nonischaemic origin, defined by NTproBNP levels of >2000 pg/mL, NYHA class III or IV and a LVEF <35% who were on stable optimized medical therapy for 3 months, were consecutively enrolled into this prospective, doubleblind, placebocontrolled trial and randomized in a 1:1:1 fashion to receive 1 g/day or 4 g/day of n3PUFA, or placebo, respectively, for 12 weeks. Results After 12 weeks of treatment, the antioxidant function of HDL, measured by the HDL inflammatory index, was found significantly impaired in the treatment group in a dosedependent fashion with 0.67 [IQR 0.491.04] for placebo vs 0.71 [IQR 0.551.01] for 1 g/day n3PUFA vs 0.98 [IQR 0.731.16] for 4 g/day n3PUFA (P for trend = 0.018). Conclusion We provide evidence for an adverse effect of n3PUFA supplementation on antioxidant function of HDL in nonischaemic heart failure patients, establishing a potential mechanistic link for the controversial outcome data on n3PUFA supplementation.(VLID)339841

In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics throughMeta-AnalysisBipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen'sd = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD

Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology

Heart failure (HF) is growing to a modern epidemic and despite advances in therapy, it still carries an ominous prognosis and a significant socioeconomic burden. Many novel agents that emerged as promising HF drugs failed to improve residual morbidity and mortality.2,3 Since developing and testing new agents has become increasingly costly,4 the concept of repurposing existing drugs for new indications has gained considerable importance. Conceptually, comorbidities such as type 2 diabetes mellitus (T2DM), obesity or chronic kidney disease, all highly prevalent in HF populations, have shifted from being innocent bystanders to drivers of HF. This applies especially to HF with preserved ejection fraction (HFpEF), a phenotype that accounts for more than 50% of HF patients and for which no effective therapy exists thus far.5,6 In particular, the prevalence of T2DM, thereby its combination with HF is rapidly increasing, mainly due to the obesity epidemic. Cardiovascular (CV) outcomes are addressed by an increasing number of clinical studies in T2DM, mainly as safety endpoints for anti-diabetic agents. Some of those drugs have beneficial CV effects independent of their glucose-lowering action. Consequently, antidiabetic agents have gained interest for their potential repurposing in HF treatment. In this context, the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) organized a workshop on HF and T2DM, focusing on the pathophysiological and therapeutic aspects of this relationship. Here, we summarize the main points raised during this workshop, providing an overview of current evidence and open issues

Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology

Heart failure (HF) is growing to a modern epidemic and despite advances in therapy, it still carries an ominous prognosis and a significant socioeconomic burden. Many novel agents that emerged as promising HF drugs failed to improve residual morbidity and mortality.2,3 Since developing and testing new agents has become increasingly costly,4 the concept of repurposing existing drugs for new indications has gained considerable importance. Conceptually, comorbidities such as type 2 diabetes mellitus (T2DM), obesity or chronic kidney disease, all highly prevalent in HF populations, have shifted from being innocent bystanders to drivers of HF. This applies especially to HF with preserved ejection fraction (HFpEF), a phenotype that accounts for more than 50% of HF patients and for which no effective therapy exists thus far.5,6 In particular, the prevalence of T2DM, thereby its combination with HF is rapidly increasing, mainly due to the obesity epidemic. Cardiovascular (CV) outcomes are addressed by an increasing number of clinical studies in T2DM, mainly as safety endpoints for anti-diabetic agents. Some of those drugs have beneficial CV effects independent of their glucose-lowering action. Consequently, antidiabetic agents have gained interest for their potential repurposing in HF treatment. In this context, the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) organized a workshop on HF and T2DM, focusing on the pathophysiological and therapeutic aspects of this relationship. Here, we summarize the main points raised during this workshop, providing an overview of current evidence and open issues