Genetic parameters of calving ease using sire-maternal grandsire model in Korean Holsteins

Objective Calving ease (CE) is a complex reproductive trait of economic importance in dairy cattle. This study was aimed to investigate the genetic merits of CE for Holsteins in Korea. Methods A total of 297,614 field records of CE, from 2000 to 2015, from first parity Holstein heifers were recorded initially. After necessary data pruning such as age at first calving (18 to 42 mo), gestation length, and presence of sire information, final datasets for CE consisted of 147,526 and 132,080 records for service sire calving ease (SCE) and daughter calving ease (DCE) evaluations, respectively. The CE categories were ordered and scores ranged from CE1 to CE5 (CE1, easy; CE2, slight assistance; CE3, moderate assistance; CE4, difficult calving; CE5, extreme difficulty calving). A linear transformation of CE score was obtained on each category using Snell procedure, and a scaling factor was applied to attain the spread between 0 (CE5) and 100% (CE1). A sire-maternal grandsire model analysis was performed using ASREML 3.0 software package. Results The estimated direct heritability (h2) from SCE and DCE evaluations were 0.11±0.01 and 0.08±0.01, respectively. Maternal h2 estimates were 0.05±0.02 and 0.04±0.01 from SCE and DCE approaches, respectively. Estimates of genetic correlations between direct and maternal genetic components were −0.68±0.09 (SCE) and −0.71±0.09 (DCE). The average direct genetic effect increased over time, whereas average maternal effect was low and consistent. The estimated direct predicted transmitting ability (PTA) was desirable and increasing over time, but the maternal PTA was undesirable and decreasing. Conclusion The evidence on sufficient genetic variances in this study could reflect a possible selection improvement over time regarding ease of calving. It is expected that the estimated genetic parameters could be a valuable resource to formulate sire selection and breeding plans which would be directed towards the reduction of calving difficulty in Korean Holsteins

Genetic Parameter Estimation in Seedstock Swine Population for Growth Performances

The objective of this study was to estimate genetic parameters that are to be used for across-herd genetic evaluations of seed stock pigs at GGP level. Performance data with pedigree information collected from swine breeder farms in Korea were provided by Korea Animal Improvement Association (AIAK). Performance data were composed of final body weights at test days and ultrasound measures of back fat thickness (BF), rib eye area (EMA) and retail cut percentage (RCP). Breeds of swine tested were Landrace, Yorkshire and Duroc. Days to 90 kg body weight (DAYS90) were estimated with linear function of age and ADG calculated from body weights at test days. Ultrasound measures were taken with A-mode ultrasound scanners by trained technicians. Number of performance records after censoring outliers and keeping records pigs only born from year 2000 were of 78,068 Duroc pigs, 101,821 Landrace pigs and 281,421 Yorkshire pigs. Models included contemporary groups defined by the same herd and the same seasons of births of the same year, which was regarded as fixed along with the effect of sex for all traits and body weight at test day as a linear covariate for ultrasound measures. REML estimation was processed with REMLF90 program. Heritability estimates were 0.40, 0.32, 0.21 0.39 for DAYS90, ADG, BF, EMA, RCP, respectively for Duroc population. Respective heritability estimates for Landrace population were 0.43, 0.41, 0.22, and 0.43 and for Yorkshire population were 0.36, 0.38, 0.22, and 0.42. Genetic correlation coefficients of DAYS90 with BF, EMA, or RCP were estimated to be 0.00 to 0.09, −0.15 to −0.25, 0.22 to 0.28, respectively for three breeds populations. Genetic correlation coefficients estimated between BF and EMA was −0.33 to −0.39. Genetic correlation coefficient estimated between BF and RCP was high and negative (−0.78 to −0.85) but the environmental correlation coefficients between these two traits was medium and negative (near −0.35), which describes a highly correlated genetic response to selection on one or the other of these traits. Genetic Trends of all three breeds tend to be towards bigger EMA or greater RCP and shorter DAYS90 especially from generations born after year 2000

L-Asparaginase delivered by Salmonella typhimurium suppresses solid tumors

Bacteria can be engineered to deliver anticancer proteins to tumors via a controlled expression system that maximizes the concentration of the therapeutic agent in the tumor. L-asparaginase (L-ASNase), which primarily converts asparagine to aspartate, is an anticancer protein used to treat acute lymphoblastic leukemia. In this study, Salmonellae were engineered to express L-ASNase selectively within tumor tissues using the inducible araBAD promoter system of Escherichia coli. Antitumor efficacy of the engineered bacteria was demonstrated in vivo in solid malignancies. This result demonstrates the merit of bacteria as cancer drug delivery vehicles to administer cancer-starving proteins such as L-ASNase to be effective selectively within the microenvironment of cancer tissue

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

The ERK and JNK pathways in the regulation of metabolic reprogramming.

Most tumor cells reprogram their glucose metabolism as a result of mutations in oncogenes and tumor suppressors, leading to the constitutive activation of signaling pathways involved in cell growth. This metabolic reprogramming, known as aerobic glycolysis or the Warburg effect, allows tumor cells to sustain their fast proliferation and evade apoptosis. Interfering with oncogenic signaling pathways that regulate the Warburg effect in cancer cells has therefore become an attractive anticancer strategy. However, evidence for the occurrence of the Warburg effect in physiological processes has also been documented. As such, close consideration of which signaling pathways are beneficial targets and the effect of their inhibition on physiological processes are essential. The MAPK/ERK and MAPK/JNK pathways, crucial for normal cellular responses to extracellular stimuli, have recently emerged as key regulators of the Warburg effect during tumorigenesis and normal cellular functions. In this review, we summarize our current understanding of the roles of the ERK and JNK pathways in controlling the Warburg effect in cancer and discuss their implication in controlling this metabolic reprogramming in physiological processes and opportunities for targeting their downstream effectors for therapeutic purposes.Brunel Research Initiative & Enterprise Fund, Brunel University of London (to CB), Kay Kendall Leukemia Fund (KKL443) (to CB), 250 Great Minds Fellowship, University of Leeds (to SP), AMMF Cholangiocarcinoma Charity (to SP and PMC), and Bloodwise (17014) (to SP and CB)

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

Genetic correlation between live body measurements and beef cutability traits in Hanwoo steers

Objective The growth, carcass and retail cut yield records on 1,428 Hanwoo steers obtained through progeny testing were analyzed in this study, and their heritability and genetic relationships among the traits were estimated using animal models. Methods Two different models were compared in this study. Each model was fitted for different fixed class effects, date of slaughter for carcass traits and batch of progeny test live measurement traits, and a choice of covariates (carcass weight in Model 1 or backfat thickness in Model 2) for carcass traits. Results The differences in body composition among individuals were deemed being unaffected by their age at slaughter, except for carcass weight and backfat thickness. Heritability estimates of body size measurements were 0.21 to 0.36. Heritability estimates of retail cut percentage were high (0.56 from Model 1 and 0.47 from Model 2). And the heritability estimates for loin muscle percentage were 0.36 from Model 1 and 0.42 from Model 2, which were high enough to consider direct selection on carcass cutability traits as effective. The genetic correlations between body size measurements and retail cut ratio (RCR) were close to zero. But, some negative genetic correlations were found with chest girths measured at yearling (Model 1) or at 24 months of age or with chest widths. Loin muscle ratio (LMR) was genetically negatively correlated with body weights or body size measurements, in general in Model 1. These relationships were low close to zero but positive in Model 2. Phenotypic correlation between cutability traits (RCR, LMR) and live body size measurements were moderate and negative in Model 1 while those in Model 2 were all close to zero. Conclusion Therefore, the body weights or linear body measurements at an earlier age may not be the most desirable selection traits for exploitation of correlated responses to improve loin muscle or lean meat yield

Genetic Parameters of Pre-adjusted Body Weight Growth and Ultrasound Measures of Body Tissue Development in Three Seedstock Pig Breed Populations in Korea

The objective of this study was to compare the effects of body weight growth adjustment methods on genetic parameters of body growth and tissue among three pig breeds. Data collected on 101,820 Landrace, 281,411 Yorkshire, and 78,068 Duroc pigs, born in Korean swine breeder farms since 2000, were analyzed. Records included body weights on test day and amplitude (A)-mode ultrasound carcass measures of backfat thickness (BF), eye muscle area (EMA), and retail cut percentage (RCP). Days to 90 kg body weight (DAYS90), through an adjustment of the age based on the body weight at the test day, were obtained. Ultrasound measures were also pre-adjusted (ABF, EMA, AEMA, ARCP) based on their test day measures. The (co)variance components were obtained with 3 multi-trait animal models using the REMLF90 software package. Model I included DAYS90 and ultrasound traits, whereas model II and III accounted DAYS90 and pre-adjusted ultrasound traits. Fixed factors were sex (sex) and contemporary groups (herd-year-month of birth) for all traits among the models. Additionally, model I and II considered a linear covariate of final weight on the ultrasound measure traits. Heritability (h2) estimates for DAYS90, BF, EMA, and RCP ranged from 0.36 to 0.42, 0.34 to 0.43, 0.20 to 0.22, and 0.39 to 0.45, respectively, among the models. The h2 estimates of DAYS90 from model II and III were also somewhat similar. The h2 for ABF, AEMA, and ARCP were 0.35 to 0.44, 0.20 to 0.25, and 0.41 to 0.46, respectively. Our heritability estimates varied mostly among the breeds. The genetic correlations (rG) were moderately negative between DAYS90 and BF (−0.29 to −0.38), and between DAYS90 and EMA (−0.16 to −0.26). BF had strong rG with RCP (−0.87 to −0.93). Moderately positive rG existed between DAYS90 and RCP (0.20 to 0.28) and between EMA and RCP (0.35 to 0.44) among the breeds. For DAYS90, model II and III, its correlations with ABF, AEMA, and ARCP were mostly low or negligible except the rG between DAYS90 and AEMA from model III (0.27 to 0.30). The rG between AEMA and ABF and between AEMA and ARCP were moderate but with negative and positive signs, respectively; also reflected influence of pre-adjustments. However, the rG between BF and RCP remained non-influential to trait pre-adjustments or covariable fits. Therefore, we conclude that ultrasound measures taken at a body weight of about 90 kg as the test final should be adjusted for body weight growth. Our adjustment formulas, particularly those for BF and EMA, should be revised further to accommodate the added variation due to different performance testing endpoints with regard to differential growth in body composition