MULTI-PARENTAL MATING DESIGN ANALYSIS: MODEL EVALUATION AND APPLICATION IN SPRING WHEAT

Conventional quantitative genetics studies have mainly focused on bi-parental mating systems. However, genetic potential of selected individuals within a segregating population may be limited due to only two parents being used for each cross. Multiple-parental mating systems have been proposed that involve three or four diverse parents. This provides a higher potential of combining desirable genes. Due to complexity of the data structure of multi-parental mating systems, analysis of variance (ANOVA) methods are not applicable in analysis. The objective of this study is to validate and apply a mixed linear model approach, minimum norm quadratic unbiased estimation (MINQUE), to analyze a widely used additive-dominance (AD) genetic model. Various simulations were conducted to validate the use of this approach. Twelve different spring wheat genotypes were used to develop populations in the study. Phenotypic data containing parents and their F2 (second filial generation) on preharvest sprouting (PHS) resistance in spring wheat (Triticum aestivum L.) developed by multi-parental crosses were used as a demonstration. The simulation study showed that a modified AD model can be used to estimate variance components in an unbiased manner within this complex data structure. Actual data analysis revealed that both additive and dominance effects were responsible for PHS resistance. Several parents associated with desirable additive effects for PHS were identified. In addition, some crosses with desirable heterozygous dominance effects were also identified, which can be used for hybrid development. Results should help breeders to obtain useful genetic information by using the methods suggested in this study

Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that presents clinicians with a diagnostic challenge. The use of natriuretic peptides to exclude a diagnosis of HFpEF has been proposed. We sought to compare HFpEF patients with N-terminal pro-brain natriuretic peptide (NT-proBNP) level above and below the proposed cut-off. Methods Stable patients (n = 30) with left ventricular (LV) ejection fraction ≥ 50% were eligible if they had a diagnosis of HF according to the European Society of Cardiology diagnostic criteria. Characteristics of patients with NT-proBNP below (≤125 pg/mL) and above (\u3e125 pg/mL) the diagnostic criterion were compared. Results There were 19 (66%) women with median age 54 years. Half were African American (16, 53%), and most were obese. There were no significant differences in clinical characteristics or medication use between groups. LV end-diastolic volume index was greater in high NT-proBNP patients (P = 0.03). Left atrial volume index, E/e\u27 ratio, and E/e\u27 ratio at peak exercise were not significantly different between NT-proBNP groups. Peak oxygen consumption (VO2), VO2 at ventilatory threshold, and ventilatory efficiency measures were impaired in all patients and were not significantly different between high and low NT-proBNP patients. Conclusions NT-proBNP was below the proposed diagnostic cut-off point of 125 pg/mL in half of this obese study cohort. Cardiac diastolic dysfunction and cardiorespiratory fitness were not significantly different between high and low NT-proBNP patients. These data indicate that excluding the diagnosis of HFpEF based solely on NT-proBNP levels should be discouraged

Dietary Fat, Sugar Consumption, and Cardiorespiratory Fitness in Patients With Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is associated with obesity and, indirectly, with unhealthy diet. The role of dietary components in HFpEF is, however, largely unknown. In this study, the authors showed that in obese HFpEF patients, consumption of unsaturated fatty acids (UFA), was associated with better cardiorespiratory fitness, and UFA consumption correlated with better diastolic function and with greater fat-free mass. Similarly, mice fed with a high-fat diet rich in UFA and low in sugars had preserved myocardial function and reduced weight gain. Randomized clinical trials increasing dietary UFA consumption and reducing sugar consumption are warranted to confirm and expand our findings

Effect of Interleukin-1 Blockade With Anakinra on Leukocyte Count in Patients With ST-Segment Elevation Acute Myocardial Infarction

Leukocytosis is a common finding in patients with ST elevation myocardial infarction (STEMI) and portends a poor prognosis. Interleukin 1-β regulates leukopoiesis and pre-clinical studies suggest that anakinra (recombinant human interleukin-1 [IL-1] receptor antagonist) suppresses leukocytosis in myocardial infarction. However, the effect of IL-1 blockade with anakinra on leukocyte count in patients with STEMI is unknown. We reviewed the white blood cell (WBC) and differential count of 99 patients enrolled in a clinical trial of anakinra (n = 64) versus placebo (n = 35) for 14 days after STEMI. A complete blood cell count with differential count were obtained at admission, and after 72 h, 14 days and 3 months. After 72 h from treatment, anakinra compared to placebo led to a statistically significant greater percent reduction in total WBC count (− 35% [− 48 to − 24] vs. − 21% [− 34 to − 10], P = 0.008), absolute neutrophil count (− 48% [− 60 to − 22] vs. − 27% [− 46 to − 5], P = 0.004) and to an increase in absolute eosinophil count (+ 50% [0 to + 100] vs. 0% [− 50 to + 62], P = 0.022). These changes persisted while on treatment at 14 days and were no longer apparent at 3 months after treatment discontinuation. We found that in patients with STEMI IL-1 blockade with anakinra accelerates resolution of leukocytosis and neutrophilia. This modulation may represent one of the mechanisms by which IL-1 blockade improves clinical outcomes

Interleukin‐1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST‐Segment–Elevation Myocardial Infarction

Background ST‐segment–elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin‐1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C‐reactive protein) levels during the first 14 days in patients with ST‐segment–elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo‐controlled, double‐blind, clinical trial in 99 patients with ST‐segment–elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39–120] versus 214 [interquartile range, 131–394] mg·day/L; P\u3c0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end‐systolic volume (median, 1.4 [interquartile range, −9.8 to 9.8] versus −3.9 [interquartile range, −15.4 to 1.4] mL; P=0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, −1.6% to 10.2%] versus 2.7% [interquartile range, −1.8% to 9.3%]; P=0.61) at 12 months. The incidence of death or new‐onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [P=0.046] and 0% versus 11.4% [P=0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P=0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P=0.016). Conclusions In patients presenting with ST‐segment–elevation myocardial infarction, interleukin‐1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01950299

Characterization of MTAP gene expression in breast cancer patients and cell lines

MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors\ub4 MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNB

C-Reactive Protein and N-Terminal Pro-brain Natriuretic Peptide Levels Correlate With Impaired Cardiorespiratory Fitness in Patients With Heart Failure Across a Wide Range of Ejection Fraction

Background: Impaired cardiorespiratory fitness (CRF) is a hallmark of heart failure (HF). Serum levels of C-reactive protein (CRP), a systemic inflammatory marker, and of N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of myocardial strain, independently predict adverse outcomes in HF patients. Whether CRP and/or NT-proBNP also predict the degree of CRF impairment in HF patients across a wide range of ejection fraction is not yet established.Methods: Using retrospective analysis, 200 patients with symptomatic HF who completed one or more treadmill cardiopulmonary exercise tests (CPX) using a symptom-limited ramp protocol and had paired measurements of serum high-sensitivity CRP and NT-proBNP on the same day were evaluated. Univariate and multivariate correlations were evaluated with linear regression after logarithmic transformation of CRP (log10) and NT-proBNP (logN).Results: Mean age of patients was 57 ± 10 years and 55% were male. Median CRP levels were 3.7 [1.5–9.0] mg/L, and NT-proBNP levels were 377 [106–1,464] pg/ml, respectively. Mean peak oxygen consumption (peak VO2) was 16 ± 4 mlO2•kg−1•min−1. CRP levels significantly correlated with peakVO2 in all patients (R = −0.350, p < 0.001) and also separately in the subgroup of patients with reduced left ventricular ejection fraction (LVEF) (HFrEF, N = 109) (R = −0.282, p < 0.001) and in those with preserved EF (HFpEF, N = 57) (R = −0.459, p < 0.001). NT-proBNP levels also significantly correlated with peak VO2 in all patients (R = −0.330, p < 0.001) and separately in patients with HFrEF (R = −0.342, p < 0.001) and HFpEF (R = −0.275, p = 0.032). CRP and NT-proBNP did not correlate with each other (R = 0.05, p = 0.426), but independently predicted peak VO2 (R = 0.421, p < 0.001 and p < 0.001, respectively).Conclusions: Biomarkers of inflammation and myocardial strain independently predict peak VO2 in HF patients. Anti-inflammatory therapies and therapies alleviating myocardial strain may independently improve CRF in HF patients across a large spectrum of LVEF

Rusty-spotted cat: 12th cat species discovered in Western Terai of Nepal

Rusty-spotted cat Prionailurus rubiginosus is the smallest wild cat, believed to be distributed only in India and Sri Lanka. Recently it was discovered from wider areas than previously thought but never recorded from Nepal. During a camera trap survey primarily targeted for tigers Panthera tigris, rusty-spotted cat was photographed multiple times on a single camera trap station in Shuklaphanta Wildlife Reserve in January and February 2016. The camera trap location is in dry-deciduous Sal Shoresa robusta forest in core area of the reserve at a distance of approximately 5 km from settlements. This is the first photographic evidence of rusty-spotted cat captured in camera traps in Nepal. Similarly, a photograph of a cat species taken by a park visitor in 2012 from Bardiya National Park was confirmed as rusty-spotted cat. With this record, Nepal has 12 felid species: tiger, common leopard Panthera pardus, snow leopard Panthera uncia, clouded leopard Neofelis nebulosa, Eurasian Lynx Lynx lynx, Asiatic golden cat Catopuma temminckii, fishing cat Prionailurus viverrinus, jungle cat Felis chaus, leopard cat Prionailurus bengalensis, marbled cat Pardofelis marmorata, Pallas's cat Otocolobus manul and rusty-spotted cat. Global Challenges (FSW