Greater Body Weight Research Articles

High prevalence of non-alcoholic fatty liver disease in patients with inflammatory bowel disease receiving anti-tumor necrosis factor therapy

Background:Non-alcoholic fatty liver disease (NAFLD) is common in patients with inflammatory bowel disease (IBD). This study evaluated the prevalence of NAFLD and the associated risk factors among IBD patients who received anti-tumor necrosis factor (TNF) therapy.Methods:Adult IBD patients receiving anti-TNF therapy (infliximab, adalimumab, certolizumab, golimumab) were enrolled. Hepatic steatosis was assessed by abdominal ultrasound. Patients with a history of excessive alcohol or recent steroid use were excluded. Univariate and multivariate analysis were performed.Results:Eighty patients, 55% male, mean age 42±15 years, were enrolled. The sonographic prevalence of NAFLD was 54% (43/80), significantly higher than the general prevalence in the US adult population (30%) (P<0.0001). NAFLD patients had a significantly higher proportion of males, as well as greater body weight and body mass index, compared to non-NAFLD. The Crohns disease activity index (CDAI) was significantly higher among patients with NAFLD. Multivariate analysis demonstrated that a higher CDAI was independently associated with NAFLD, with an odds ratio of 1.6 (95% confidence interval 1.05-2.44; P=0.03).Conclusions:The presence of IBD is strongly associated with NAFLD. We identified a high prevalence of NAFLD among IBD patients receiving anti-TNF. CDAI was independently associated with hepatic steatosis. Further studies are still needed to evaluate the pathophysiology of NAFLD development and disease progression among IBD populations.

Milk yield and composition of primiparous recipient cows influence the performance and carcass ultrasonography of Nellore calf

ABSTRACT This study investigates the influence of the breed of primiparous recipient cows on milk yield and composition during the lactation stage, as well as evaluating the carcass and performance characteristics of their calves at weaning. The experiment was conducted in a commercial Nellore herd with two groups of primiparous recipient beef cattle, Nellore (n = 11) and ½ Angus × Nellore (n = 11). Variables were measured monthly from birth to weaning. Days in milk affected milk intake and composition. There was an effect of the interaction of breed and time on milk fat, protein and lactose, measured in g/kg of milk. Calves from Angus primiparous cows had greater body weight, average daily gain (ADG), longissimus muscle area (LMA) and longissimus weight-to-width ratio than others, since those traits are associated with milk yield. In contrast, considering area/100 kg, backfat and marbling, the Nellore cows delivered similar calves to the Angus cows, due to the better quality of their milk. Milk intake was positively correlated with ADG, BW and LMA, but negatively correlated with milk protein, fat and lactose. The nutrients in milk were positively correlated with milk intake, and body weight was positively correlated with LMA, weight-to-width ratio, backfat, milk intake and ADG.

Double Running Suture Line Repair in Primary Umbilical Hernias - Analysis after 282 Cases

There is an ongoing debate as to which patients presenting with an umbilical hernia should be operated with the sole suture technique or augmented by mesh. After treating most of our patients for a long period uniformly with a double running suture line, the aim of this study was to evaluate the performance of this strategy - especially in patients with larger defects. From 1/2004 to 4/2017, all patients operated on for an umbilical hernia were identified through our hospital information system (KIS). The relevant documents for each case - such as operation and discharge reports, anaesthesia protocol, and information on the clinical course were extracted and the critical parameters entered into a database program (FileMaker® 12.0). Adult patients (≥ 18 y) with a double running suture line, excluding recurrences and surgery simultaneously to minimally invasive interventions, receiving surgery on umbilical defects ≤ 2 cm (size 1) were compared to those with defects > 2 cm (size 2). Long-time results were gathered from the KIS, follow-up investigations, questionnaires and telephone interviews. Chi-square and Mann-Whitney U tests were applied; p < 0.05 was considered significant. 515 operations for umbilical hernias were identified, of which 282 were primary cases with double running suture. The follow-up was 77%. Only cases with follow-up information were considered. Patients with size 1 (n = 147) were significantly younger than patients with size 2 (n = 69; 51 vs. 54 years; p = 0.0012), had a lower BMI (29 vs. 33; p = 0.003) and tended to have lower ASA score (2 vs. 2; p = 0.0837). Complications were seen in 8/147 (5%) vs. 4/69 (6%) cases, respectively (p = 0.9174). The recurrence rate after a median of 4,6 years was in 6/147 in size 1 (4%) vs. 4/69 (6%) in size 2 (p = 0.5759). The use of a double running suture line with non-absorbable material with umbilical hernias led to good results in our patients. Repair of primary umbilical hernias was mostly successful, independently of the size of the defect, even in older patients with greater body weight.

Nutritional evaluation and productivity of supplemented sheep grazing in semiarid rangeland of northeastern Brazil.

Sheep production systems in Brazilian caatinga rangelands require supplementation adapted to changes in floristic and chemical composition as dry seasons progress. Meeting sheep nutritional needs in extensive semiarid systems is challenging because of sheep dietary preferences and habits. The objective of this trial was to evaluate the substitutive effect of concentrate supplementation on grazing sheep in the Brazilian caatinga rangeland and its consequences on performance in different seasons. The trial was conducted from March to August 2013 at Embrapa Goat and Sheep in Sobral, Ceará State, Brazil. Thirty-two Brazilian Somali multiparous ewes were submitted to estrus synchronization and controlled breeding. At the start of the trial, ewes averaged 30.45 + 2.60kg body weight (BW). Ewes were divided into four groups and individually offered 0, 200, 350, or 500g supplement head-1 day-1. Intake prediction and digestibility trials were evaluated at three periods: rainy season (April), transition rainy-dry (June), and dry season (August). Sheep weights were taken every 14days to measure their performance from late gestation until weaning. Ewe BW and body condition score changes were determined too. Lamb BW changes were also measured every 14days from birth through weaning. A completely randomized design with split plot arrangement using eight replications was used for intake and digestibility measurements. The differences between supplement offered (0, 200, 350, and 500g sheep-1) and season (rainy, transition rainy-dry, and dry) were submitted to analyses of variance and multiple means were separated, where differences were detected, using the Tukey's test. During lactation up through weaning, ewes supplemented at 500gday-1 had greater BW than ewes without supplement. Ewes supplemented with 200g concentrate head-1 day-1 had 9.1% greater (P ≤ 0.05) BW at weaning and their lambs had 19.7% greater birth and 16.6% heavier wean BW despite lower dry matter intake compared to unsupplemented animals. Supplementation with 200g concentrate increased carrying capacity by 28.8% during the dry season and by 20.5% during the rainy season. This study confirmed that in the dry season, when quality of rangeland forages decreases, supplementation contributes to greater DMI, improves postpartum and lactation BW recovery of ewes, and contributes to greater lamb birth and wean weights. Moreover, supplementation leads to feed substitution effects that may increase rangeland resilience by mitigating overgrazing. Supplementation with 200g concentrate can also prevent negative energy balance for grazing animals, improving longer postnatal recovery, longer intervals between parturitions, fewer double and is necessary to ensure a better BW at birth to lambs.

Effects of Achyranthes bidentata Polysaccharides on Intestinal Morphology, Immune Response, and Gut Microbiome in Yellow Broiler Chickens Challenged with Escherichia coli K88.

The present study was conducted to investigate the effects of dietary Achyranthes bidentata polysaccharide (ABPS) supplementation on performance, immune response, intestinal mucosal morphology, and gut microbiome in yellow-feathered broilers challenged with Escherichia coli K88. A 2 × 2 factorial design was used for the trial. Two hundred and forty one-day-old female broilers were randomly assigned to four treatments: (1) negative-control broilers were fed by a basal diet and saline (NG); (2) positive-control broilers were fed by a basal diet and orally challenged with 108 CFU E. coli K88 (CNG); (3) ABP group broilers were fed by a basal diet containing ABPS (500 mg/kg of feed) and saline; (4) CABP group broilers were fed by a basal diet containing ABPS (500 mg/kg of feed) and orally challenged with 108 CFU E. coli K88. Growth performance, serum biochemical indexes, immune responses, intestinal mucosal morphology, and cecal microbial community structure were evaluated. The ABP group had greatest body weight (BW), average daily body weight gain (ADG), and intestinal villus height compared to other treatments (p < 0.05). The CABP group had a higher villus height/crypt depth ratio (V/C) compared with other treatments (p < 0.05). The expression levels of NF-κB were lower in the ABP group. The CNG group had higher Escherichia coli and Enterococcus contents in cecal samples compared to other treatments (p < 0.05). Serum glucose, uric acid, TNF-α, and Secretory Immunoglobulin A (S-IgA) levels were higher in broilers challenged with E. coli (p < 0.001) than that with saline. Broilers challenged with E. coli had reduced taxa richness in the cecal samples. Sequencing of 16S rRNA genes in cecal samples revealed that a lower proportion of Firmicutes and a higher proportion of Proteobacteria were detected in the broilers challenged with E. coli. Compared with the controls, dietary ABPS supplementation increased serum total protein, albumin, and S-IgA levels, but decreased serum glucose, uric acid, and TNF-α levels in broilers (p < 0.05). Diet supplemented with ABPS increased the Firmicutes/Bacteroidetes ratio and the abundance of Ruminococcaceae and Lachnospiraceae, and altered cecal microbiota community structure. These results suggest that ABPS can promote growth performance and improve intestinal morphology and microbiota community structure in broilers challenged with E. coli K88.

Factors associated with prevalent and incident foot pain: data from the Tasmanian Older Adult Cohort Study

ObjectivesTo describe factors associated with prevalent and incident foot pain in a population-based cohort of older adults (n = 1092). Study designLongitudinal observational study. Main outcome measuresPrevalent foot pain, incident foot pain after 5 years. MethodsPotential correlates included demographic factors, anthropometry, leg strength, metabolic factors, steps per day (using pedometer), pain at 6 other sites, and psychological wellbeing. Data were analysed using log binomial models. ResultsParticipants were aged 50–80 years (mean 63 years), 49% male, mean body mass index (BMI) 27.8 ± 4.7 at baseline. The prevalence of foot pain at baseline was 38% and the incidence of new pain over 5 years was 20%. BMI, pain at other sites (neck, hands, knees, pain at three or more sites), and poorer psychological wellbeing were independently associated with baseline foot pain. Baseline BMI and pain in the neck, hands, and knees were independently associated with incident foot pain; but change in weight or BMI, total number of painful joints and psychological wellbeing were not. Self-reported diabetes and cigarette smoking were not associated with prevalent or incident foot pain. ConclusionsThis study demonstrates that greater body weight and joint pain at multiple sites were consistently associated with prevalent foot pain and predict incident foot pain. Addressing excess body mass and taking a global approach to the treatment of pain may reduce the prevalence and incidence of foot pain in older adults.

Luteolin Targets the Toll-Like Receptor Signaling Pathway in Prevention of Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice.

This study was to investigate the protective role of luteolin on inflammation-mediated metabolic diseases, focusing on the role of luteolin in the modulation of the Toll-like receptor (TLR) signaling pathway. C57BL/6J mice were fed a normal, high-fat, or high-fat + 0.005% (w/w) luteolin diet for 16 weeks. Luteolin improved chronic low-grade inflammation by modulating the TLR signaling pathway, resulting in reduced pro-inflammatory cytokines and macrophage accumulation. A positive relationship was detected between gene expressions of Tlr5, Map2k7, Mapk12, Mapk13, and Mapk9 and lipogenesis in epididymal white adipose tissue (eWAT) of luteolin-treated mice, which was linked to attenuation of hepatic lipotoxicity by increasing free fatty acid (FFA) flux to the WAT. Luteolin prevented fibrosis by decreasing extracellular matrix accumulation and cathepsin gene expressions, while enhancing the hepatic antioxidant system. Emr1 and Ccl7, important markers inducing low-grade inflammation, were affected by advanced age and greater body weight, which were normalized by luteolin treatment. Luteolin improved insulin resistance by normalizing pancreatic islet dysfunction and differentially modulating the plasma glucagon-like peptide-1 and gastric inhibitory polypeptide levels. Our results suggest that luteolin ameliorates diet-induced obesity and its comorbidities. Overall, this study provides novel insights into the effect of luteolin on the links among adiposopathy, insulin resistance, hepatic steatosis, and fibrosis.

Digestive tract morphometry and breast muscle microstructure in spent breeder ducks maintainedin a conservation programme of genetic resources

Abstract. The objective of this study was to compare three genetic groups of ducks: P9 (French Pekin), K2 (bred from wild mallards – Anas platyrhynchos L. and Pekin duck), and KhO1 (hybrid of Khaki Campbell drake and Orpington Fauve duck) after two breeding seasons for body weight and length, length of intestine and its segments, percentage of other internal organs, and breast muscle microstructure. The study used 60 ducks, 20 birds (10 males and 10 females) from each genetic group. At 110 weeks of age, P9 ducks exhibited significantly (p&lt;0.05) greater body weight and length, and length of intestine and its segments (except for colon length) compared to K2 and KhO1 ducks. KhO1 ducks had significantly shorter jejunum and ileum compared to K2 birds. The lighter K2 and KhO1 ducks had significantly greater relative length of intestine and its segments. In P9 ducks, liver, heart, and gizzard were heavier and spleen percentage in body weight significantly lower than in K2 and KhO1 birds. KhO1 ducks had a significantly higher percentage of proventriculus compared to the other duck groups. The different genetic origins of the ducks had no effect on microstructural characteristics of m. pectoralis superficialis except for perimysium and endomysium thickness. Our study provided information about differences in the digestive tract morphometry and breast muscle microstructure of ducks from three genetic groups after two reproductive seasons, which are maintained in a conservation programme of genetic resources in Poland.

Morphological variation associated with dispersal capacity in a tree‐killing bark beetleDendroctonus ponderosaeHopkins

AbstractIntrinsic factors influencing the dispersal of insect pests during outbreaks are poorly understood, yet these factors need to be quantified to parameterize dispersal in models that predict population spread. The present study related wing and body morphology of female mountain pine beetles (Dendroctonus ponderosae) to flight distance, as measured by flight mill bioassays.Beetles that flew long distances (&gt; 11 km) had a greater body weight and larger wings than beetles that flew short distances (&lt; 1 km). These heavier female beetles should also be more capable pioneers because other studies have shown that body weight is positively correlated with lipid content.Wing and body morphology of females are significant predictors of flight distance; heavy beetles with large wings generally flew further than smaller beetles, although this relationship is heteroscedastic. Dispersion of flight distance values increases with wing loading (weight/wing area) as a result of a cohort of ‘lazy’ individuals that fly short distances (&lt; 1 km) regardless of flight phenotype.The observed morphology explained less than 20% of the variation in flight capacity, indicating a substantial contribution from other intrinsic factors that remain to be investigated. The present study may have implications for dispersal modelling, providing estimates of flight capacity using morphological measurements.

Effect of supplementation level on performance of growing Nellore and its influence on pasture characteristics in different seasons

Eighty-four Nellore bulls (269 ± 27 kg; 13 months) were used in a completely randomized design to evaluate different supplementation strategies on the performance of growing Nellore cattle grazing Panicum maximum cv. Tanzania in the rainy season and rainy-to-dry season transition. In the rainy season, 42 animals received mineral salt (MS) ad libitum and 42 received protein supplement (PR) at 1 g kg−1 body weight (BW). In the rainy-to-dry season transition, 28 animals received MS, 28 received PR at 1 g kg−1 BW, and 28 received a protein-energy (PE) supplement at 3 g kg−1 BW. In the rainy season, the PR supplement increased average daily gain (ADG), providing a significant increase of 17 kg in final BW. In the first period of the rainy-to-dry season transition, PE promoted better performance than MS, while PR did not differ from the two other treatments. In the second period of the rainy-to-dry season transition, PE and PR increased ADG by 41% and 31%, respectively, compared with MS. In the third period, all supplements differed from each other. Bulls fed PE had greater final BW compared with animals fed PR and MS. In conclusion, during the rainy season, PR supplementation should be provided even under good pasture conditions. Also, during the rainy-to-dry season transition, protein-energy supplementation is recommended to compensate for quantitative and qualitative deficiencies of the pasture.HighlightsNellore cattle being backgrounded on pasture with supplementation has greater body weight in the feedlot entry.Supplementation is recommended to compensate for quantitative and qualitative deficiencies of the pasture.Supplementation promotes a positive response in animal performance.

Abstract 004: Caloric Restriction Prevents the Increase in Body Weight but not Hypertension in ALMS1 (Alström syndrome 1) Knockout Rat

In humans, mutations in the ALMS1 gene cause obesity, diabetes and kidney disease. The mechanisms causing these alterations are unclear. We generated ALMS1 knockout (KO) rats in the Dahl salt-sensitive (SS) genetic background and found that ALMS1 KO are hypertensive (telemetry or tail-cuff) and develop obesity and insulin resistance. We found that ALMS1 is expressed in the kidney where it regulates thick ascending limb NaCl reabsorption. However, it is unclear whether the hypertension in the ALMS1KO occurs prior to or after the development of obesity and insulin resistance. W e hypothesize that hypertension in the ALMS1 KO rats is primarily caused by a renal defect and not secondary to obesity . We studied the effect of control feeding or caloric restriction (CR) in body weight (BW), blood glucose, glucose tolerance test (GTT) and systolic blood pressure (SBP) by tail-cuff in ALMS1 KO and wild-type Dahl SS (WT) littermate rats. A control group of ALMS1 KO and WT rats received 30 g/day regular chow (0.4% Na). A caloric restricted (CR) group received 20% less food (24 g/day) of a custom diet with 20% higher Na, vitamins and minerals, thereby matching Na intake. At 7 weeks of age, ALMS1 KO rats had similar BW (KO: 209±13 g vs. WT: 182±15 g), baseline glucose (KO: 88±3 vs. WT: 75±7 mg/dL, N.S.) and GTT. Importantly, SBP was higher in ALMS1 KO rats (KO: 156±5 vs. WT: 143+3 mmHg, p&lt;0.05). By 11 weeks of age, KO rats had a greater BW (KO: 393±9 vs. WT:344±5 g, p&lt;0.05) and higher SBP (KO:186±7 vs. WT:162±7 mmHg, p&lt;0.05). Baseline glucose was higher (KO:101±5 vs. WT:65±4 mg/dL, p&lt;.001) and peak levels of glucose during GTT were higher (KO:464±21 vs. WT:341±33, mg/dL, p&lt;.0.05) in KO rats. Caloric restriction for 4 weeks prevented the difference in BW between KO and WT (KO:359±8 vs. WT:340±3 g, N.S.) and lowered BW compared to control feeding (KO control: 393±9 vs. KO- CR: 359±8 g, p&lt;0.05). However SBP remained higher than in WT (KO:178±9 vs. WT:151±3 mmHg, p&lt;0.05) and was not different from KO fed control diet. GTT was also not different between KO control and KO-CR. We conclude that the hypertension in rats with ALMS1 deficiency occurs prior to obesity and metabolic syndrome, and that CR prevents the increase in BW but does not prevent hypertension or improve insulin resistance in this rat model.

Effects of dietary supplementation with combinations of organic and medium chain fatty acids as replacements for chlortetracycline on growth performance, serum immunity, and fecal microbiota of weaned piglets

This study investigated the effects of dietary combinations of organic acids and medium chain fatty acids (MCFAs) as replacements for chlortetracycline on the growth performance, serum immunity, and fecal microbiota of weaned piglets. Over 28 days, 144 piglets (8.09 ± 0.11 kg) were allocated to four treatments: CON (basal diet), CTC (CON + 0.075 g/kg chlortetracycline), OAMF (CON + 0.2% organic acid blend 1), and COAMF (CON + 0.2% organic acid blend 1 + 0.6% or 0.4% organic acid blend 2). Compared with the CON group, piglets in the COAMF group had greater body weight on day 28 (P < 0.05), greater average daily gain during days 1–28 (P < 0.05), and lower feed conversion ratio during days 1–14 and 1–28 (P < 0.05). The diarrhea rate in the CTC group during day 1–14 was significantly lower than in the CON group (P < 0.05). The concentration of serum IgG on day 14 and serum IgA on day 28, and the concentration of serum T-AOC on days 14 and 28, were higher and the concentration of serum MDA on day 28 was lower (P < 0.05) in piglets supplemented with combinations of organic acids and MCFAs compared with basal diet. Compared with the CON group, OAMF and COAMF groups both had increased and decreased relative abundances of Firmicutes and Proteobacteria, respectively (both P < 0.05). Moreover, supplementation with blends of organic acid and MCFAs significantly increased the relative abundance of Lactobacillus and Faecalibacterium (P < 0.05). In summary, dietary supplementation with combinations of organic acids and MCFAs improved growth performance, reduced diarrhea rate, and enhanced serum immunity by regulating the microbiota of weaned piglets. Thus, such combinations can be fed as potential alternatives to chlortetracycline to weanling piglets.

A proof-of-concept study to evaluate the efficacy and safety of BTI320 on post-prandial hyperglycaemia in Chinese subjects with pre-diabetes

BackgroundGalactomannan(s) are plant-derived fiber shown to reduce post-prandial blood glucose by delaying intestinal absorption of carbohydrates and slowing down gastric emptying. We examined glucose-lowering effects of BTI320, a propriety fractionated mannan(s) administered as a chewable tablet before meal in a proof-of-concept study in Chinese subjects with prediabetes.MethodsSixty Chinese adults aged 18–70 years with either impaired fasting glucose, impaired glucose tolerance, or glycated haemoglobin 5.7–6.4% (39-46 mmol/mol), were randomly assigned in 2:2:1 ratio to either BTI320 8 g (high dose), BTI320 4 g (low dose) or matching-placebo three times daily before meal for 16 weeks. The primary endpoint was change in fructosamine in subjects treated with BTI320 compared with placebo from baseline to week 4. Indices of glycaemic variability based on continuous glucose monitoring (CGM) and standard meal tolerance test were explored in secondary analyses.ResultsOf 60 subjects randomized, 3 subjects discontinued study treatment prematurely. In intention-to-treat analysis, no significant differences in change in serum fructosamine between low or high dose BTI320 and placebo were observed. Using random effect models, adjusted for variability by meals, treatment with low dose BTI320 was associated with reduction in 1-h (p < 0.01), 2-h (p = 0.01) and 3-h (p = 0.02) post-prandial incremental glucose area-under-curve and post-meal maximum glucose (p = 0.03) compared with placebo. Subjects receiving low dose BTI320 had greater body weight reduction than placebo group.ConclusionsBTI320 did not change fructosamine levels compared with placebo. BTI320 reduced glycaemic variability based on CGM indices.Trial registrationThe study was registered at www.clinicaltrials.gov, reference number NCT02358668 (9 February 2015).

Efficacy of yeast and multi-strain probiotic alone or in combination on growth performance, carcass traits, blood biochemical constituents, and meat quality of broiler chickens

This study was conducted to investigate the efficacy of yeast (Saccharomyces cerevisiae) and multi-strain probiotic (Lactobacillus acidophilus, Bacillus subtilis, and Aspergillus oryzae) alone or in combination on the growth performance, carcass measurements, serum biochemical constituents, meat antioxidant capacity, and fatty acid composition in broiler chickens. In this experiment, three hundred thirty-six 7-D-old broiler chickens were randomly assigned to 4 treatments: control (CON), 0.5% dried yeast (DY), 0.5% probiotic (PRO), or 0.25% DY and 0.25% PRO (DY-PRO) with 6 pens per treatment and 14 broiler chickens per pen. At 35 d of age, the DY-PRO treatment had greater body weight and dressing percentage, and better feed conversion ratio (P < 0.05) than the CON treatment, but was not different from the PRO treatment. Lower abdominal fat (P < 0.001) was observed in the DY, PRO, and DY-PRO treatments compared to the CON treatment at 35 d of age. Broiler chickens fed the DY, PRO or DY-PRO diet had greater serum total protein, globulin, and glucose, but lower total lipids and cholesterol (P < 0.001) than those fed the CON diet at d 35 of age. The inclusion of DY-PRO increased crude protein and decreased crude fat of the breast meat (P < 0.05), followed by the PRO and DY diets as compared with the CON diet. At 35 d of age, the DY and DY-PRO treatments had lower malondialdehyde and greater glutathione peroxidase values of the breast meat (P < 0.001) than the CON and PRO treatments. The DY, PRO or DY-PRO diet increased polyunsaturated fatty acid (PUFA; P < 0.05), n-3 fatty acids (P < 0.001) and PUFA/saturated fatty acids ratio (P < 0.05), but decreased n-6/n-3 ratio (P < 0.001) in the breast meat compared with the CON diet at the end of the experiment. The current study indicated that the inclusion of DY-PRO beneficially affects the growth performance, meat composition, antioxidant capacity, and fatty acid profile of the meat, followed by the PRO and DY diets. The DY-PRO combination could be used as a functional feed additive in broiler chickens.

Abstract B066: Development of paired small-molecule drug conjugates for prostate cancer precision theranostics

Abstract Objectives: Traditional cancer chemotherapy is normally associated with systemic toxicity due to the lack of tumor-targeting specificity. Recent efforts have therefore focused on targeted therapy to reduce such systemic toxicity. We have recently developed a pair of 18/19F-labeled theranostic small-molecule drug conjugates (18/19F-T-SMDCs) for prostate cancer precision theranostics, which consists of a prostate-specific membrane antigen (PSMA) specific ligand for prostate cancer targeting, a cytotoxic drug (DM1, with high antimitotic cytotoxicity at subnanomolar range) for chemotherapy, and an 18F imaging unit via a lysine-PEG trifunctional linker for PET imaging or a nonradioactive 19F unit for therapy in order to overcome the dosage gap between diagnostic and therapeutic agents. The18/19F-T-SMDCs have been demonstrated to retain the PSMA binding affinity, exhibit high cell uptake in PSMA-positive cells, display an appreciable level of internalization in a time-dependent manner, and be capable of specifically imaging PSMA-expressing cancer xenografts in mice. Here we evaluated the in vitro cytotoxicity and in vivo therapeutic potency of the18/19F-T-SMDCs. Methods: The in vitro cytotoxicity of 19F-T-SMDC was measured by crystal violet cell growth assay in PSMA-positive LNCaP cells and PSMA-negative PC-3 cells. The DM1 free drug was included in the assay as an internal positive standard to compare the toxicity of 19F-T-SMDC in these two cell lines. In vivo treatment study was performed in SCID mice bearing PSMA-positive PC3-PIP subcutaneous tumors to evaluate both imaging and therapeutic performance of 18/19F-T-SMDCs (DM1). The treatment started when the average tumor volumes were in the range of 100 - 200 mm3 (length × width × height × 0.523), with intravenous injection of 15 or 40 nmol 19F-T-SMDC in 10% ethanol solution per mouse (n = 8) for three times a week for total four injections. The control group of mice received 10% ethanol solution plus 0.075 nmol 19F-T-SMDC (DM1) following the same injection schedule (n = 3). PET imaging with 18F-T-SMDC (DM1) was conducted before (Day 0: 18F-T-SMDC only) and during the 1st-dose treatment (Day 1: coinjection of 18/19F-T-SMDC) for both 15 and 40 nmol groups (n = 3). Besides the PET imaging with 18F-T-SMDC, concurrent FDG PET imaging was also conducted in the 15 nmol group mice (n = 3) before and post treatment (week 4) to monitor the treatment responses. Results: The PSMA-positive LNCaP cells exhibited higher toxicity from 19F-T-SMDC (DM1) than PSMA-negative PC-3 cells. In comparison to free DM1 drug, the 19F-T-SMDC (DM1) was less toxic in both LNCaP and PC-3 cells. The reduced toxicity of the T-SMDC is desirable to alleviate the acute side effects of the drug (DM1) to normal tissues. For treatment study, 19F-T-SMDC (DM1) showed controllable acute toxicity, with the body weight loss all within 15%. While the 40-nmol group showed a greater body weight loss than the 15-nmol group, both groups started their body weight recovery from Day 18. In contrast, the control group showed no body weight loss until Day 10 when the tumor burden became severe. The average tumor sizes of both high- and low-dose treatment groups stopped increasing by Day 7. After then, all tumors started shrinking over the course of the treatment. Meanwhile, the control group was observed with fast and continuous tumor growth. Although the increased dose did not benefit the tumor reduction, the high-dose treatment group exhibited delayed tumor recurrence compared to the low-dose group. Conclusions: The 18/19F-T-SMDCs retain PSMA binding affinity, exhibit PSMA-dependent toxicity, and are capable of specifically imaging PSMA-positive cancer xenografts in mice. They also show effective therapeutic performance in in vivo tumor treatment study, and can be served as a promising strategy for prostate cancer precision theranostics Citation Format: Bing Guan, Yunkou Wu, Jingyue Yang, Yahong Xiong, Jer-Tsong Hsieh, Guiyang Hao, Xiankai Sun. Development of paired small-molecule drug conjugates for prostate cancer precision theranostics [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B066.

Serum 25-Hydroxyvitamin D Concentrations Are Inversely Correlated with Hepatic Lipid Content in Male Collegiate Football Athletes

Lower serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with more weight and fat mass gain in adults in the general population, but it is unknown whether this is the case in collegiate football athletes with greater body weight. This study aimed to investigate associations of serum 25(OH)D concentrations with body fat and ectopic fat accumulation, and to determine which fat indicators are closely related to serum 25(OH)D in male collegiate football athletes. Thirty-four collegiate athletes aged 21 years were recruited. Serum 25(OH)D concentrations and the levels of visceral fat area (VFA), vastus lateralis intramyocellular lipid (IMCL), extramyocellular lipid (EMCL), and intrahepatic lipid (IHCL) were measured. Serum 25(OH)D concentrations were negatively associated with the IHCL values (r = −0.372, p = 0.030), and the relationship remained after adjustment for several factors (r = −0.378, p = 0.047). Additionally, multiple stepwise regression analysis of IHCL content as the dependent variable indicated that 25(OH)D concentrations were a stronger predictor of IHCL content (β = −0.363, p = 0.030) than % body fat and VO2peakFFM. Higher serum 25(OH)D concentrations are more closely related to lower IHCL content rather than any other fat indicators, suggesting that increasing serum 25(OH)D concentrations may have some effect that inhibits lipid accumulation in hepatic tissue, especially in heavy athletes.

Effects of early nutrition and transport of 1-day-old chickens on production performance and fear response

The importance of optimal early life conditions of broilers to sustain efficient and healthy production of broiler meat is increasingly recognized. Therefore, novel husbandry systems are developed, in which immediate provision of nutrition post hatch is combined with on-farm hatching. In these novel systems, 1-day-old-chick handling and transport are minimized. To study whether early nutrition and reduced transport are beneficial for broiler performance and behavior, the effects of early or delayed nutrition and post-hatch handling and transport were tested from hatch until 35 d of age, in a 2 × 2 factorial arrangement. In total, 960 eggs were hatched in 36 floor pens. After hatch, chicks were given immediate access to water and feed (early nutrition) or after 54h (delayed nutrition). Eighteen hours after hatch, chicks remained in their pens (non-transported control), or were subjected to short-term handling and transport to simulate conventional procedures. Subsequently, chicks returned to their pens. Compared with delayed-fed chickens, early-fed chickens had greater body weight up to 21 d of age, but not at slaughter (35 d of age). No effects of transport or its interaction with moment of first nutrition were found on performance. At 3 d post hatch, transported, early-fed chicks had a greater latency to stand up in a tonic immobility test than transported, delayed-fed chicks, but only in chicks that were transported. At 30 d post hatch, however, latency was greater in transported, delayed-fed chickens than in transported, early-fed chicks. This may indicate long-term deleterious effects of delayed nutrition on fear response in transported chickens. It is concluded that early nutrition has mainly beneficial effects on performance during the first 2 wk post hatch, but these beneficial effects are less evident in later life. The combination of transport and early nutrition may influence the chicken's strategies to cope with stressful events in early and later life.

Nr4a1 and Nr4a3 Knock Out Mice Have Impaired Glucose Clearance and Beta-Cell Function under High-Fat Feeding

We have shown that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for beta cell mitochondrial respiration and fuel utilization, and that loss of either factor impedes fuel utilization and insulin secretion. We have also demonstrated that prolonged culture of INS-1 832/13 beta cells with progressively increasing concentrations of palmitic acid results in decreased Nr4a1 and Nr4a3 expression, impaired mitochondrial respiration, and reduced insulin secretion. Here we explore the effect of 20-week high fat diet on wild type mice and mice deficient for either Nr4a1 or Nr4a3. Nr4a1 and Nr4a3 knock out mice have greater body weight than wild type animals when on a high fat diet. Mice deficient for Nr4a1 or Nr4a3 have no significant change in non-fasting blood glucose measurements as compared to wild type under normal chow conditions. Non-fasting blood glucose was elevated in both Nr4a1 and Nr4a3 knock out mice under high fat feeding conditions. Fasting glucose tolerance tests also demonstrate that Nr4a1 and Nr4a3 knock out mice have impaired glucose tolerance as compared to wild type animals under high fat feeding. Mitochondrial respiration of muscle, liver, adipose and islets are impaired as compared to wild type controls under high fat feeding. Glucose stimulated insulin secretion is impaired in islets from Nr4a1 or Nr4a3 knock out mice fed a high fat diet. These data demonstrate changes in various metabolic tissues as a result of high fat feeding and deletion of the Nr4a orphan nuclear receptors, demonstrating that they play a critical role in systemic fuel utilization. Disclosure C.J. Smith: None. K.B. Kener: None. J.S. Tessem: None.

Weight Loss Outcomes with Species-Specific Dual GLP-1R/GCGR Agonists in Animal Models

Dual agonism of glucagon-like peptide-1 receptor and glucagon receptor (GLP-1 R/GCGR) was shown to reduce body weight. Species-specific dual GLP-1 R/GCGR agonist peptides (SSDA), structurally based on exendin-4 and carrying a fatty acid side-chain for half-life extension, or the selective GLP-1 R agonist liraglutide (lira) were administered to diet-induced obese (DIO) mice twice daily for 32 days, and to DIO and diabetic cynomolgus monkeys once daily for 43 days. Potencies of the SSDA and lira on mouse and monkey GLP-1 receptors were in the single-digit picomolar range. Body weight change was greater with SSDA than with lira in mice (-21.1 ± 2.1% vs. -12.9 ± 1.4%) and monkeys (-8.2 ± 1.2%; p&amp;lt;0.001 vs. -5.1 ± 1.1%; p&amp;lt;0.001; Figure). Indirect calorimetry in mice showed increased total energy expenditure (TEE) in those treated with SSDA, caused not only by increased fat oxidation but also by increased oxidation of carbohydrates. Lira significantly increased TEE, but significantly less than SSDA. These data support the mechanistic view that weight loss with SSDA does not result exclusively from reduced food intake but also from increased energy expenditure induced by GCGR activity. In murine and primate models, dual GLP-1 R/GCGR agonism with SSDA led to greater body weight loss than GLP-1 R alone. This represents a novel dual mechanism of action with potential for the treatment of obesity. Disclosure R. Elvert: Employee; Self; Sanofi. M. Bossart: Employee; Self; Sanofi. B. Zhang: None. A. Kannt: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. M. Wagner: Employee; Self; Sanofi. T. Haack: Employee; Self; Sanofi-Aventis Deutschland GmbH. A. Evers: Employee; Self; Sanofi. A. Dudda: Employee; Self; Sanofi. M. Lorenz: None. S. Keil: Employee; Self; Sanofi. P.J. Larsen: Employee; Self; Sanofi.

ASSOCIATION OF CLINICAL, PSYCHOEMOTIONAL STATUS AND THE PATHOGENETIC THERAPY WITH THE DEVELOPMENT OF REMISSION IN ADULT PATIENTS WITH JUVENILE RHEUMATOID ARTHRITIS

Relevance. The study of the frequency of remission in adult patients with JRA treated in accordance with the "Unified clinical protocol for medical care for patients with juvenile rheumatoid arthritis" is relevant.&#x0D; Objective. The aim of our study was to evaluate the association of the clinical, psycho-emotional state and the pathogenetic therapy with the development of remission in adult patients with JRA.&#x0D; Materials and methods. 168 adult patients with JRA were examined at the transition period of the health care and adolescents. A retrospective analysis of medical records was performed to evaluate clinical symptoms and laboratory data in childhood and evaluated the clinical status, duration of the disease, activity on the JADAS and DAS-28 scales, quality of life, depression and alexithymia by scales SF-36, PHQ-9, TAS- 20, bone mineral density and methods of treatment in childhood and in adulthood.&#x0D; Results. All patients were divided into 2 groups: Group I - 138 patients (82.1%) with active disease at the time of examination, and II group - 30 patients (17.9%) who achieved remission. Patients who achieved remission did not differ by age at the time of the study, although the prevalence of women (58.1%) in the I group was determined, compared with 31.0% in the II group. Patients in both groups did not differ in height, however, patients with remission had a greater body weight (p &lt;0.01) and BMI (p &lt;0.01). There were no differences between the groups in the level of RF and A-CCP, ANA and the presence of HLA-B27, as well as in total cholesterol, LDL-cholesterol, glucose as risk factors for atherosclerosis (all p&gt; 0.05). Patients with active disease had lower BMD in femoral neck and in ultradistal forearm area (all p &lt;0.05). There were no difference in the the appointment of the IBT in doth groups. However, patients with remission more often did not receive GC in history (p &lt;0.001) and at the time of examination (p &lt;0.001), which is explained by less activity in the onset of the disease (p &lt;0.05). Both groups did not differ in either the duration of the DMARD therapy, nor on the doses of methotrexate and sulfosalazine. Of the 53 patients with RF(+)/RF(-) polyarthritis - the most prognostically unfavorable variant of JRA, had arthritis &gt; 3 joints (p &lt;0.01), symmetrical arthritis (p &lt;0.05), higher ESR ( p &lt;0,05) compared patients with remission, and the absence of differences in the levels of CRP and JADAS.&#x0D; Conclusions. Patients with JRA in adulthood in 82.1% continue to have an active disease of varying degrees. The negative influence of the active disease on the BMD is found, mainly in the area of ​​femoral neck and ultradistal forearm in adult patients with active JRA compared with patients in remission. The significant influence of active disease in adulthood on the quality of life according to the SF-36 questionnaire was determined such as physical well-being, physical, role and social functioning, bodily pain, general health, and mental health compared with the group of patients in remission. An increase level of depression was found by PHQ-9 questionnaire in the I group compared to II group, although they did not differ in the level of Alexithymia. Patients who achieved remission compared with patients with active polyarthritis, were less likely to take GC in adulthood and reseived a higher dose of methotrexate.