Effect of type of diet on blood and plasma taurine concentrations, cardiac biomarkers, and echocardiograms in 4 dog breeds

BACKGROUND: Associations of diet with dilated cardiomyopathy are under investigation. OBJECTIVES: That cardiac assessment would show abnormalities in healthy dogs eating grain-free (GF) diets or diets with Food and Drug Administration (FDA)-listed ingredients of concern (peas, lentils, or potatoes) as top 10 ingredients (FDA-PLP), but not in dogs eating grain-inclusive (GI) diets or diets without FDA-listed ingredients of concern (PLP) in the top 10 ingredients (NoFDA-PLP). ANIMALS: One hundred eighty-eight healthy Doberman Pinschers, Golden Retrievers, Miniature Schnauzers, and Whippets. METHODS: This study was an observational cross-sectional study. Echocardiograms, cardiac biomarkers, and blood and plasma taurine concentrations were compared between dogs eating GF (n = 26) and GI (n = 162) diets, and between FDA-PLP (n = 39) and NoFDA-PLP (n = 149) diets, controlling for age and breed. Demographic characteristics, murmurs, genetic status, and ventricular premature complexes (VPCs) during examination were compared between dogs eating different diet types. RESULTS: No differences in echocardiographic variables, N-terminal pro-B-type natriuretic peptide or whole blood taurine were noted between dogs eating different diet types. Dogs eating GF diets had higher median high-sensitivity cardiac troponin I (hs-cTnI) (GF 0.076 ng/mL [Interquartile range (IQR), 0.028-0.156] vs. GI 0.048 [IQR, 0.0026-0.080]; P \u3c .001) and higher median plasma taurine (GF 125 nmol/mL [IQR, 101-148] vs GI 104 [IQR, 86-123]; P = .02) than dogs eating GI diets. Dogs eating FDA-PLP diets had higher median hs-cTnI (0.059 ng/mL [IQR, 0.028-0.122]) than dogs eating NoFDA-PLP diets (0.048 [IQR, 0.025-0.085]; P = .006). A greater proportion of dogs eating FDA-PLP diets (10%) had VPCs than dogs eating NoFDA-PLP diets (2%; P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE: Higher hs-cTnI in healthy dogs eating GF and FDA-PLP diets might indicate low-level cardiomyocyte injury

Comparison of three methods of feeding sows in gestation and the subsequent effects on lactation performance

A total of 684 sows from breeding groups over six weeks were used to compare three methods of feeding during gestation and to assess the subsequent effects on lactation performance. Control gilts and sows were fed according to body condition based on a scale of 1 to 5, (1=thin, 5=fat). Sows were visually assessed for body condition at breeding and were assigned a daily feed allowance to achieve a body condition score of 3 at farrowing. Sow body condition was evaluated every two weeks throughout gestation, and feed allowance was adjusted as required. Treatment two used feeding levels based on backfat thickness (measured between d 0 and 5 after breeding) and weight at weaning for sows or weight at service for gilts. Feed allowance was calculated to achieve a target backfat of 19 mm at farrowing. Sow feeding level remained constant from d 0 to 101 of gestation. Feed allowances were based on modeled calculations of energy and nutrient requirements to achieve target sow maternal weight and backfat gain. Treatment three was identical to treatment two except that feeding pattern was altered for thin sows and gilts (\u3c15 mm at service) in an attempt to reach 19 mm by d 36 of gestation. Sows were weighed at the previous weaning and gilts at-service and again between d 112 and 114 of gestation. Backfat was measured between d 0 and 5 and again between d 108 and 113 of gestation. Sows on treatments two and three achieved backfat of 19 and 19.1 mm at farrowing, respectively, while control sows numerically tended to have greater backfat at farrowing (20 mm). On average, sows targeted to gain large amounts (6 to 9 mm) of backfat in gestation failed to achieve target gains regardless of feeding method. Feeding sows in gestation based on backfat (treatments two and three) resulted in a higher proportion of sows in the target backfat range of 17 to 21 mm at farrowing and a lower percentage of fat sows (\u3e21 mm) but no difference in the percentage of thin sows (\u3c17 mm) compared to the standard method of feeding based on body condition. Gestation feeding method had no effect on performance during lactation. Feed intake in lactation was lower for high backfat sows (\u3e21 mm) at farrowing compared to sows with \u3c21 mm. The high proportion of sows in the optimum backfat category demonstrates that feeding based on backfat and body weight has potential for facilitating more precise gestation feeding.; Swine Day, 2003, Kansas State University, Manhattan, KS, 200

Regulation of microRNA biosynthesis and expression in 2102Ep embryonal carcinoma stem cells is mirrored in ovarian serous adenocarcinoma patients

<p>Abstract</p> <p>Background</p> <p>Tumours with high proportions of differentiated cells are considered to be of a lower grade to those containing high proportions of undifferentiated cells. This property may be linked to the differentiation properties of stem cell-like populations within malignancies. We aim to identify molecular mechanism associated with the generation of tumours with differing grades from malignant stem cell populations with different differentiation potentials. In this study we assessed microRNA (miRNA) regulation in two populations of malignant Embryonal Carcinoma (EC) stem cell, which differentiate (NTera2) or remain undifferentiated (2102Ep) during tumourigenesis, and compared this to miRNA regulation in ovarian serous carcinoma (OSC) patient samples.</p> <p>Methods</p> <p>miRNA expression was assessed in NTera2 and 2102Ep cells in the undifferentiated and differentiated states and compared to that of OSC samples using miRNA qPCR.</p> <p>Results</p> <p>Our analysis reveals a substantial overlap between miRNA regulation in 2102Ep cells and OSC samples in terms of miRNA biosynthesis and expression of mature miRNAs, particularly those of the miR-17/92 family and clustering to chromosomes 14 and 19. In the undifferentiated state 2102Ep cells expressed mature miRNAs at up to 15,000 fold increased levels despite decreased expression of miRNA biosynthesis genes Drosha and Dicer. 2102Ep cells avoid differentiation, which we show is associated with consistent levels of expression of miRNA biosynthesis genes and mature miRNAs while expression of miRNAs clustering to chromosomes 14 and 19 is deemphasised. OSC patient samples displayed decreased expression of miRNA biosynthesis genes, decreased expression of mature miRNAs and prominent clustering to chromosome 14 but not 19. This indicates that miRNA biosynthesis and levels of miRNA expression, particularly from chromosome 14, are tightly regulated both in progenitor cells and in tumour samples.</p> <p>Conclusion</p> <p>miRNA biosynthesis and expression of mature miRNAs, particularly the miR-17/92 family and those clustering to chromosomes 14 and 19, are highly regulated in both progenitor cells and tumour samples. Strikingly, 2102Ep cells are not simply malfunctioning but respond to differentiation specifically, a mechanism that is highly relevant to OSC samples. Our identification and future manipulation of these miRNAs may facilitate generation of lower grade malignancies from these high-grade cells.</p

Improving tumor budding reporting in colorectal cancer : a Delphi consensus study

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.Peer reviewe

EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression.

Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2-20 induces airway mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in airway mucin expression in other systems; therefore, we hypothesized that the RSV 2-20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2-20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2-20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from "mucogenic" strains. RSV 2-20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced airway mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced mucin expression, suggesting EGFR is a potential target for RSV disease

Evaluation of Colloids and Activation Agents for Determination of Melamine Using UV-SERS

UV-SERS measurements offer a great potential for environmental or food (detection of food contaminats) analytics. Here, the UV-SERS enhancement potential of various kinds of metal colloids, such as Pd, Pt, Au, Ag, Au-Ag core-shell, and Ag-Au core-shell with different shapes and sizes, were studied using melamine as a test molecule. The influence of different activation (KF, KCl, KBr, K 2SO 4) agents onto the SERS activity of the nanomaterials was investigated, showing that the combination of a particular nanoparticle with a special activation agent is extremely crucial for the observed SERS enhancement. In particular, the size dependence of spherical nanoparticles of one particular metal on the activator has been exploited. By doing so, it could be shown that the SERS enhancement increases or decreases for increasing or decreasing size of a nanoparticle, respectively. Overall, the presented results demonstrate the necessity to adjust the nanoparticle size and the activation agent for different experiments in order to achieve the best possible UV-SERS results

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic–pharmacodynamic (PK–PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research