Ependymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and ...supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (
FGFR1/FGFR3
) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that
FGFR1
and
FGFR3
were both widely expressed across all molecular groups.
FGFR3
mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (
FGF1
,
FGF2)
across all EPN subtypes while
FGF9
was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that
FGFR3
was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found
FGFR3
to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the
FGFR1/3-IIIc
variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) compromises pig performance. However, increasing standardized ileal digestible Lys per Mcal metabolizable energy (SID Lys:ME) ...above requirement has been shown to mitigate reduced performance seen during a porcine reproductive and respiratory syndrome (PRRS) virus challenge. The objective of this study was to evaluate the effects of increasing the dietary SID Lys:ME from 100% National Research Council (NRC) requirement to 120% of the requirement in vaccinated (vac+; modified live vaccine Ingelvac PRRS) and non-vaccinated (vac−; no PRRS vaccine) grower pigs subjected to a PRRSV challenge. In addition, the dietary formulation approach to achieve the 120% ratio by increasing Lys relative to energy (HL) or diluting energy in relation to Lys (LE) was evaluated. This allowed us to test the hypothesis that pigs undergoing a health challenge would have the ability to eat to their energy needs. Within vaccine status, 195 mixed-sex pigs, vac+ (35.2 ± 0.60 kg body weight BW) and vac− (35.2 ± 0.65 kg BW) were randomly allotted to one of three dietary treatments (2.67, 3.23, or 3.22 g SID Lys:ME) for a 42-d PRRS virus challenge study representing 100%, 120%, and 120% of NRC requirement, respectively. Pigs were randomly allotted across two barns, each containing 24 pens with 7 to 10 pigs per pen (8 pens per diet per vaccine status). On day post-inoculation 0, both barns were inoculated with PRRSV and started on experimental diets. Within vaccine status, weekly and overall challenge period pig performance were assessed. In both vac+ (P < 0.05) and vac− (P < 0.05) pigs, the HL and LE diets increased end BW and overall average daily gain (ADG) ADG compared with pigs fed the control diet (P < 0.05). Overall, average daily feed intake (ADFI) during the challenge period was greater (P < 0.05) for pigs fed the LE diet compared with pigs fed control and HL treatments, regardless of vaccine status (20% and 17% higher ADFI than the control in vac+ and vac− pigs, respectively). The HL vac+ pigs had the greatest gain to feed (G:F) compared with the control and LE pigs (0.438 vs. 0.394 and 0.391 kg/kg, respectively; P < 0.01). Feed efficiency was not impacted (P > 0.10) by treatment in the vac− pigs. In summary, PRRSV-challenged grower pigs consumed feed to meet their energy needs as indicated by the increase in ADFI when energy was diluted in the (LE) diet, compared with control pigs. In both PRRS vac+ and vac− pigs subsequently challenged with PRRSV, regardless of formulation approach, fed 120% SID Lys:ME diets resulted in enhanced overall growth performance.
Abstract
Although pork producers typically aim to optimize growth rates, occasionally it is necessary to slow growth, such as when harvest facility capacity is limited. In finishing pigs, numerous ...dietary strategies can be used to slow growth so pigs are at optimal slaughter body weights when harvest facility capacity and/or access is restored. However, the impact of these diets on pork carcass quality is largely unknown. Thus, this study aimed to evaluate the efficacy of dietary strategies to slow growth in late finishing pigs and evaluate their effects on carcass composition and pork quality. Mixed-sex pigs (n = 897; 125 ± 2 kg BW) were randomly allotted across 48 pens and assigned to 1 of 6 dietary treatments (n = 8 pens/treatment): (1) Control diet representative of a typical finisher diet (CON); (2) diet containing 3% calcium chloride (CaCl2); (3) diet containing 97% corn and no soybean meal (Corn); (4) diet deficient in isoleucine (LowIle); (5) diet containing 15% neutral detergent fiber (NDF) from soybean hulls (15% NDF); and (6) diet containing 20% NDF from soybean hulls (20% NDF). Over 42 d, pen body weights and feed disappearance were collected. Pigs were harvested in 3 groups (14, 28, and 42 d on feed) and carcass data collected. From the harvest group, 1 loin was collected from 120 randomly selected carcasses (20 loins/treatment) to evaluate pork quality traits. Overall, ADG was reduced in CaCl2, Corn, and 20% NDF pigs compared with CON pigs (P < 0.001). However, ADFI was only reduced in CaCl2 and 20% NDF pigs compared with CON (P < 0.001). Feed efficiency was reduced in CaCl2 and Corn pigs compared with CON (P < 0.001). Hot carcass weights were reduced in CaCl2 pigs at all harvest dates (P < 0.001) and were reduced in Corn and 20% NDF pigs at days 28 and 42 compared with CON pigs (P < 0.001). In general, CaCl2 and 20% NDF diets resulted in leaner carcasses, whereas the Corn diet increased backfat by 42 d on test (P < 0.05). Loin pH was reduced and star probe increased in CaCl2 pigs compared with CON pigs (P < 0.05); no treatments differed from CON pigs regarding drip loss, cook loss, color, firmness, or marbling (P ≥ 0.117). Overall, these data indicate that several dietary strategies can slow finishing pig growth without evidence of behavioral vices. However, changes to carcass composition and quality were also observed, indicating quality should be taken into consideration when choosing diets to slow growth.
Heat stress causes morbidity and mortality in humans and animals and threatens food security by limiting livestock productivity. Inflammatory signaling may contribute to heat stress-mediated skeletal ...muscle dysfunction. Previously, we discovered increased circulating endotoxin and intramuscular oxidative stress and TNF-α protein abundance, but not inflammatory signaling following 24 and 72 h of heat stress. Thus the purpose of this investigation was to clarify the role of inflammatory signaling in heat-stressed skeletal muscle. Crossbred gilts (n = 8/group) were assigned to either thermal neutral (24°C), heat stress (37°C), or pair-fed thermal neutral (24°C) conditions for 12 h. Following treatment, animals were euthanized, and the semitendinosus red (STR) and white (STW) were recovered. Heat stress did not alter inflammatory signaling in STW. In STR, relative heat shock protein abundance was similar between groups, as was nuclear content of heat shock factor 1. In whole homogenate, relative abundance of the NF-κB activator inhibitory κB kinase-α was increased by heat stress, although abundance of NF-κB was similar between groups. Relative abundance of phosphorylated NF-κB was increased by heat stress in nuclear fractions. Activator protein-1 (AP-1) signaling was similar between groups. While there were few differences in transcript expression between thermal neutral and heat stress, 80 and 56% of measured transcripts driven by NF-κB or AP-1, respectively, were increased by heat stress compared with pair-fed thermal neutral. Heat stress also caused a reduction in IL-6 transcript and relative protein abundance. These data demonstrate that short-term heat stress causes inflammatory signaling through NF-κB in oxidative, but not glycolytic, skeletal muscle.
Abstract
Sow mortality, as the result of pelvic organ prolapse (POP), has been increasing in the last decade in the U.S. swine industry. The objective of this study was to identify potential ...biological markers associated with risk of POP in sows. We hypothesized that sows differing in perineal score (PS) from PS1–PS3 (PS1—a presumed low POP risk; PS2—a presumed moderate POP risk; and PS3—a presumed high POP risk) would differ in circulatory biomarkers of inflammation and hormonal profiles. On gestation week 15, 2,864 individual sows were assigned a PS, and subsequently, 1.0%, 2.7%, and 23.4% of PS1, PS2, or PS3 sows, respectively, experienced POP. During PS assignment at days 107–116 of gestation, blood samples were collected from sows on two farms of similar genetics, feed sources, and health status. Whole blood was subjected to complete blood count (CBC) analysis (n = 212) and steroid hormones were measured in serum from a subset (n = 110) of animals assigned PS3 parity matched to PS1. Lipopolysaccharide-binding protein (LBP), tumor necrosis factor-alpha (TNF-α), haptoglobin, C-reactive protein (CRP), and creatine kinase (CK) levels were also evaluated. Complete blood count analysis revealed decreased (P ≤ 0.05) mean platelet volume (3.9%), lymphocytes (6.5%), and monocytes (7.5%) in PS3 compared to PS1 sows. Increased (P ≤ 0.02) abundance of androstenedione (13.4%), androsterone (18.2%), estrone (24.8%), and 17β-estradiol (26.2%) was observed in PS3 compared to PS1 sows. Additionally, a 25.8% increase (P = 0.04) in LBP in PS3 compared to PS1 sows was observed. Many dynamic physiological changes occur in sows during late gestation as they approach farrowing. The data presented herein demonstrate that distinct differences in concentrations of circulating biomarkers exist between late gestation sows at high or low risk for POP and may serve as a useful tool for understanding the etiology of POP and evaluation of mitigation strategies.
Abstract
Three experiments (EXP) were conducted to determine the effect of feed additives on performance, intestinal integrity, gastrointestinal volatile fatty acids (VFA), and energy and nutrient ...digestion in nonchallenged nursery pigs. In EXP 1, 480 pigs (6.36-kg body weight, BW) were placed into 96 pens with 5 pigs/pen, and allotted to 1 of 10 dietary treatments: 1) negative control containing no feed additive (NC), 2) NC + 44 mg chlortetracycline and 38.5 mg tiamulin/kg diet (CTsb), 3) NC + 5% resistant potato starch (RSpo), 4) NC + 5% soluble corn fiber (SCF), 5) NC + 5% sugar beet pulp (SBP), 6) NC + 0.30% fatty acid mix (FAM), 7) NC + 0.10% phytogenic blend of essential oils and flavoring compounds (PHY), 8) NC + 50 mg Cu and 1,600 mg zinc oxide/kg diet (CuZn), 9) NC + 5% resistant corn starch (RScn), and 10) NC + 0.05% β-glucan (BG) for 28 d. There was no impact of dietary treatment on BW gain or feed intake (P ≥ 0.22). Pigs fed diets containing SCF, CTsb, and RSpo resulted in microbial community differences compared to pigs fed the NC (P < 0.05). In EXP 2, 48 barrows (12.8 kg BW) were selected at the end of EXP 1 and fed the same dietary treatments they had previously received: 1) NC, 2) NC + 5% RScn, 3) NC + 5% SCF, and 4) NC + FAM for 8 d. There was no effect of feeding diets containing RScn, SCF, or FAM on in vivo intestinal permeability (P ≤ 0.21). Ileal or colon pH, concentrations of VFA did not differ due to dietary treatment (P ≥ 0.36), but pigs fed diets containing FAM resulted in a greater butyric acid concentration in the cecum compared to pigs fed the NC (P ≤ 0.05). In EXP 3, 156 pigs (6.11 kg BW) were placed into 52 pens with 3 pigs/pen and allotted to 1 of 4 dietary treatments arranged in a factorial manner: 1) NC, 2) NC + 5% RSpo, 3) NC + 0.30% FAM, and 4) NC + 5% RSpo + 0.30% FAM for 24 d. Feeding pigs diets containing RSpo did not affect BW gain (P = 0.91) while pigs fed diets containing FAM grew improved BW gain (P = 0.09). Colonic butyric acid concentrations were greater in pigs fed diets containing RSpo (P = 0.03), while pigs fed diets containing FAM exhibited reduced total VFA concentrations (P = 0.11). The results indicate that supplementing diets with digestively resistant but fermentable fibers, short- and medium-chain fatty acids, or antibiotics do not have a consistent effect, positive or negative, on markers of intestinal integrity or barrier function, intestinal VFA patterns, ATTD of energy and nutrients, or on pig performance.
Abstract
Heat stress negatively affects performance and intestinal integrity of pigs. The objective of this study was to characterize the effects of diurnal heat stress (dHS) on nursery-grower pig ...performance, intestinal integrity, and lipopolysaccharide (LPS) translocation. Forty-eight nursery-grower gilts, individually penned, were randomly assigned to two treatments. Twenty-four pigs were then exposed to dHS for 3 d, 6 h at 38°C and 18 h at 32°C, at 40–60% humidity. The remaining pigs were maintained under thermal neutral (TN) conditions. Changes in pig rectal temperatures (Tr), respiration rates (RR), performance, and blood parameters were evaluated. Additionally, ex vivo ileum integrity was assessed with the Ussing chamber by measuring transepithelial resistance (TER), and 4 kDa fluorescein isothiocyanate (FITC)–dextran (FD4) and FITC–LPS mucosal to serosal flux. As expected, dHS increased pig Tr and RR (P < 0.05) and reduced pig performance (P < 0.05) on the 3-d period. Compared with TN, ileum TER (P = 0.04), FITC–LPS (P < 0.001), and FD4 (P = 0.011) permeability were significantly increased due to dHS. Compared with TN pigs, dHS increased serum endotoxin by 150% (P = 0.031). Altogether, 3-d dHS significantly reduced pig performance and intestinal integrity and increased blood endotoxin concentrations.
In the United States swine industry, preweaning mortality represents the highest mortality rate of any production phase, nearly half attributed to crushing. The overarching aim of this study was to ...determine if enrichment ropes would entice neonatal piglets away from the sow and reduce preweaning mortality. Rope enrichments were provided to 161 piglets from 26 sows after farrowing. Ropes were dipped in sunflower oil (
= 7), semiochemical (
= 8), or milky cheese (
= 11). Piglet purposeful rope investigations, weight gain, and mortality were recorded. On Day 2, 75% of piglets touched the enrichment at least once, and frequency ranged from 1 to 21 investigations across all treatments. Frequency (
= 0.20) and duration (
= 0.21) of investigations were not affected by treatment. Preweaning litter average weight gain did not differ between treatments (
= 0.71). MC (milky cheese) piglets had the lowest percent mortality when the enrichment ropes were present (Days 2 to 5,
= 0.01), and SC (semiochemical) piglets had the lowest percent mortality after the enrichment ropes were removed (Days 6 to weaning,
< 0.0001). This proof-of-concept study highlights the potential value of neonatal piglet environmental enrichment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Prolonged environment-induced hyperthermia causes morbidities and mortality in humans and animals and appears to cause organ-specific injury and dysfunction. We have previously determined autophagic ...dysfunction and apoptotic signaling in oxidative skeletal muscle following prolonged hyperthermia. The aim of this investigation was to extend our knowledge regarding the early chronology of heat stress-mediated apoptotic and autophagic signaling in oxidative skeletal muscle. We hypothesized that 2, 4, and 6 h of hyperthermia would increase apoptosis and autophagy in oxidative skeletal muscle compared to thermoneutral (TN) conditions. Pigs were assigned to four groups (n = 8/group) and exposed to environmental heat stress (37 °C) for 0, 2, 4, or 6 h. Immediately following environmental exposure animals were euthanized and the red portion of the semitendinosus was collected. Markers of apoptotic signaling were increased following 2 h of heating but returned to baseline thereafter, while caspase 3 activity remained elevated 2–3 fold (p < .05) throughout the hyperthermic period. Heat stress increased (p < .05) markers of autophagic activation, and nucleation as well as autophagosome formation and degradation linearly throughout the heating intervention. In addition, 6 h of hyperthermia increased (p < .05) markers of mitophagy. These data suggest that apoptotic signaling precedes increased autophagy during acute heat stress in oxidative skeletal muscle.
•Two hours of heat stress caused a transient increase in apoptotic signaling.•Two through six hours of hyperthermia stimulated a robust increase in autophagy.•Short-term heat stress appears mechanistically distinct from long-term heat stress.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant disease in the swine industry, and increasing soybean meal (SBM) consumption during this disease challenge may improve ...performance. Our objectives were to determine the impact of SBM level on apparent total tract (ATTD) and ileal (AID) digestibility during PRRSV infection and to determine ileal basal endogenous losses (BEL) during PRRSV infection. Forty PRRSV negative gilts were fitted with a T-cannula in the distal ileum. Treatments were arranged in a 2 × 2 factorial with high and low SBM (HSBM, 29% vs. LSBM, 10%), with and without PRRSV (n = 6/treatment). The remaining pigs (n = 8/challenge status) were fed a N-free diet. Chromic oxide was used as an indigestible marker. On day post inoculation (dpi) 0, at 47.7 ± 0.57 kg BW, 20 pigs were inoculated with live PRRSV; 20 control pigs were sham inoculated. Infection was confirmed by serum PCR. Feces were collected at dpi 5 to 6 and dpi 16 to 17, and ileal digesta collected at dpi 7 to 8 and dpi 18 to 19. Feed, feces, and digesta were analyzed for DM, N, and GE. Digesta and feed were analyzed for AA. Data were analyzed in a 2 × 2 + 2 factorial design to determine main effects of diet and PRRSV and their interaction. Data from N-free fed pigs were analyzed separately to determine BEL and hindgut disappearance due to PRRSV infection. All control pigs remained PRRSV negative. There were no interactions for AID of AA; however, HSBM reduced DM, GE, Lys, and Met AID and increased Arg and Gly AID during both collection periods (P < 0.05). At dpi 7 to 8 only, PRRSV reduced DM and GE AID (P < 0.05). At 7 to 8 dpi, BEL of Arg, Ala, and Pro were reduced (P < 0.05) due to PRRSV by 64%, 39%, and 94%, respectively. At dpi 18 to 19, BEL of Thr tended (P = 0.06) to be increased in PRRSV-infected pigs; however, no other differences were observed. Pigs fed LSBM had increased Lys, Met, Thr, Trp, and Pro standardized ileal digestibility (SID), primarily at 7 to 8 dpi. At 7 to 8 dpi, PRRSV reduced Arg, Gly, and Pro SID (P < 0.01), and SID Pro continued to be reduced by 17% at dpi 18 to 19. Compared with HSBM pigs, LSBM reduced hindgut disappearance of DM and GE at dpi 5 to 8 and dpi 16 to 19, while N disappearance was reduced at dpi 5 to 8. There were no differences between control and PRRSV N-free fed pigs. Altogether, SBM inclusion impacts SID of AA and hindgut disappearance of nutrients, regardless of PRRSV. In contrast, there is minimal impact of PRRSV on BEL, and therefore, SID of most AA are not different.
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