Body Weight Of Animals Research Articles

PSIII-2 Evaluation of medium-chain fatty acids on just-weaned piglet performance and diarrhea scores: A nursery trial

Abstract Weaning is one of the most stressful events for commercial pigs. The transition from mother’s milk (animal proteins) to a solid diet based on plant proteins, the reduction in lactose intake and the decline in HCl secretion by the digestive system of the piglet result in a sudden and significant increase in stomach pH as well as an increased risk of post-weaning diarrhea. The aim of this trial was to evaluate whether the use of a blend of medium-chain fatty acids (MCFAs) on top-off conventional nursery diets would improve zootechnical performance and intestinal problems in just-weaned piglets. Piglets [n = 624, 21-d of age, 6.5 kg body weight (BW), (♂ Fast Duroc x ♀ Fast 275)] were housed in 26 pens of an experimental nursery. Each pen (24 pigs/pen, with a starting density of 3.0 ft2/pig) was equipped with a height-adjustable water sucker, a water bowl and fitted with a single feeder-bin. Females and males were allocated to each pen, according to 3 BW categories (heavy, medium, and light). During a 46-d period of trial, the piglets (13 replicated pens per treatment) were allotted to a conventional 5 phases feeding program with 2 kg/MT of chlortetracycline (22%) and 400 g/MT of tiamuline (1.78%; CON). These basal diets contained 2,500 ppm Zn in Phases #1, 2, and only 2,000 ppm Zn in phase #3. Phases #1 to 3 were also supplemented with Ca-butyrate (1 kg/MT) and a blend of protected acidifiers (1 kg/MT). The treated group consisted to the basal diet (CON) supplemented with a blend of medium-chain fatty acids (MCFAs) at 1.0 or 0.75 kg/MT for Phases #1, 2,3 and Phases #4, 5, respectively and supplying of a proprietary blend of caprylic, capric, and lauric acids. Daily feed consumption, weekly pig pen BW, dead and removed pigs and daily diarrhea evaluation index were completed. Data are analyzed by an ANOVA model including treatment and pen as fixed and random effects, respectively. Pairwise comparisons were completed with a Chi-square test. The overall results are presented in Table 1. At the end of wk 2 and 3, animals receiving MCFAs had a better average daily gain (ADG; P < 0.05) than CON. Therefore, at wk 2, 3 and 4, MCFAs animals BW were heavier than CON ones (P < 0.05). Average daily feed intake (ADFI) was not significantly different for the overall duration of the trial (P > 0.05). However, at weeks 2 and 3, MCFAs piglets had a greater ADFI than CON ones (P < 0.05). The daily diarrhea index of the MCFAs group was less than CON at wk 3 (P < 0.05). In this trial, the significant improvement of diarrhea index on just-weaned MCFAs treated piglets could explain the significant better growth during the first 3 wk of nursery.

Allometric scaling of the parameters characterizing venous return surface in the generalized framework of circulatory equilibrium

Study objective: In the generalized framework of circulatory equilibrium (GCE), the integrated cardiac output (CO) curve characterizes the pumping abilities of the left and right hearts, whereas the venous return (VR) surface characterizes the preloading properties of the systemic and pulmonary circuits. Equilibrium CO (= VR), left (PLA) and right (PRA) atrial pressures are predicted from the intersection between the CO curve and VR surface. In VR surface, VR is theoretically related with stressed blood volume (V), PLA and PRA as: VR =V/W − Gs × PRA − Gp × PLA, where Gs and Gp is a ratio of systemic (Cs) and pulmonary (Cp) vascular compliance to W (time constant of the systemic and pulmonary circuits), respectively. However, there was a concern whether the standard parameters can be applicable to animals with different body size including human. The objective of this study is to experimentally investigate whether an allometric scaling of the parameters (Gs, Gp, W, Cs, Cp) of the VR surface is feasible. Hypothesis: Kleiber’s law indicates that an animal's metabolic rate scales to the 3⁄4 power of the animal's body weight (BW). Based on this, we hypothesize that Cs and Cp may be proportionate to BW, W may be proportionate to BW1/4. Hence, Gs and Gp may be proportionate to BW3/4. Methodology: Seven mongrel dogs (BW 26±2.8 kg) and 4 beagles (BW 9±0.5 kg) were anesthetized, and their left and right hearts were replaced by dual mechanical pumps. While V was kept constant, by controlling the speed of the fluid pumps, VR (ml/min), PLA and PRA (mmHg) were changed variably over a wide range to obtain six sets of VR, PLA and PRA. After the change of a known amount of V (4 mL/kg), six sets of VR, PLA and PRA were obtained in a similar manner. Using 12 sets of VR, PLA and PRA, we obtained Gs, Gp, W, Cs, and Cp using regression analysis in each animal. Finally, we analyzed relations between BW and all these parameters using regression analysis over the 11 animals. Data: Gs (r2=0.73, p value for independent variable piv<0.01; p value for intercept, pi=0.57) and Gp (r2=0.81, piv<0.01, pi=0.64) were proportionate to BW3/4. Cs (r2=0.37, piv=0.027, pi=0.40) and Cp (r2=0.61, piv<0.01, pi=0.48) were proportionate to BW. However, W (r2=-0.11, piv=0.90, pi=0.17) was not associated with BW1/4. Summary of results: All parameters characterizing VR surface except for W were significantly associated with BW. W did not show a significant association with BW, potentially due to the low variations of BW. Conclusions: Allometric scaling of VR surface may be feasible and effective in future clinical application of GCE. NTT Research, Inc. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Size-dependent deleterious effects of nano- and microplastics on sperm motility

IntroductionGrowing concerns regarding the reproductive toxicity associated with daily life exposure to micro-/nano-plastics (abbreviated as MNPs) have become increasingly prevalent. In reality, MNPs exposure involves a heterogeneous mixture of MNPs of different sizes rather than a single size. MethodsIn this study, an oral exposure mouse model was used to evaluate the effects of MNPs of four size ranges: 25–30 nm, 1–5 µm, 20–27 µm, and 125–150 µm. Adult male C57BL/6 J mice were administered environmentally relevant concentrations of 0.1 mg MNPs/day for 21 days. After that, open field test and computer assisted sperm assessment (CASA) were conducted. Immunohistochemical analyses of organ and cell type localization of MNPs were evaluated. Testicular transcriptome analysis was carried out to understand the molecular mechanisms. ResultsOur result showed that MNPs of different size ranges all impaired sperm motility, with a decrease in progressive sperm motility, linearity and straight-line velocity of sperm movement. Alterations did not manifest in animal locomotion, body weight, or sperm count. Noteworthy effects were most pronounced in the smaller MNPs size ranges (25–30 nm and 1–5 µm). Linear regression analysis substantiated a negative correlation between the size of MNPs and sperm curvilinear activity. Immunohistochemical analysis unveiled the intrusions of 1–5 µm MNPs, but not 20–27 µm and 125–150 µm MNPs, into Leydig cells and testicular macrophages. Further testicular transcriptomic analysis revealed perturbations in pathways related to spermatogenesis, oxidative stress, and inflammation. Particularly within the 1–5 µm MNPs group, a heightened perturbation in pathways linked to spermatogenesis and oxidative stress was observed. ConclusionsOur data support the size-dependent impairment of MNPs on sperm functionality, underscoring the pressing need for apprehensions about and interventions against the escalation of environmental micro-/nano-plastics contamination. This urgency is especially pertinent to small-sized MNPs.

A novel preclinical model of human lung cancer cachexia

Most patients with lung cancer are afflicted with cancer cachexia (CC), a syndrome characterized by wasting of muscle and fat tissues, which leads to poor treatment response and increased mortality. Pre-clinical models used to study CC often do not mimic the human condition, which may explain why there are no approved treatments for CC. To overcome this barrier, we sought to develop a model of lung CC that better recapitulates the pathoetiological characteristics of human lung CC using mice with a tamoxifen-inducible, lung epithelial cell (club cell)-specific KrasG12D allele ( G12D mice). We hypothesized that this model would mimic human CC in tumor location and burden, rate of progression, and tumor-driven tissue wasting. Following induction by tamoxifen injection, adenocarcinomas developed in the terminal bronchioles as early as 3.5 weeks post-induction and were accompanied by loss of 15% of animal body weight over a 12-week period. This weight loss began at 6 weeks and yielded a slow rate of CC progression (-1.9%/week) relative to currently available lung CC models (-5-10%/week). Body weight loss resulted from reductions in hindlimb muscle mass (18-30%) and profound depletion of inguinal and gonadal adipose tissue depots (60-70%) compared to age-matched wild-type (WT) littermates. At 6 weeks post-induction, fat tissue was reduced at the tissue and cellular levels while reductions in hindlimb muscle weight and fiber size were not observed. This fat loss corresponded with increased serum glycerol levels at 6 and 12 weeks, a metabolic characteristic that was also found in patients with lung cancer receiving treatment. Lung organoids were developed from G12D and WT mice. G12D organoids exhibited similarities in gene expression to human lung tumors ( RNAseq) and their conditioned medium (CM) elicited glycerol release from cultured 3T3L1 adipocytes compared to CM from WT organoids, suggesting that tumor-derived factors may contribute to early adipose tissue atrophy. Collectively, these findings suggest that G12D mice may be a valuable model, well-suited to identify mechanisms leading to CC and test preventative therapies. NIH R01 AR065826(MJT), NCI R21 CA283492(MJT), T32- HL076122-18(DBS/MEP), R01 CA273238 (YJ-H) and the University of Vermont Cancer Center. Funding support for RNAseq provided by Zymo Impact Initiative Grant (DBS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Global nitrous oxide emissions from livestock manure during 1890-2020: An IPCC tier 2 inventory.

Nitrous oxide (N2O) emissions from livestock manure contribute significantly to the growth of atmospheric N2O, a powerful greenhouse gas and dominant ozone-depleting substance. Here, we estimate global N2O emissions from livestock manure during 1890-2020 using the tier 2 approach of the 2019 Refinement to the 2006 IPCC Guidelines. Global N2O emissions from livestock manure increased by ~350% from 451 [368-556] Gg N year-1 in 1890 to 2042 [1677-2514] Gg N year-1 in 2020. These emissions contributed ~30% to the global anthropogenic N2O emissions in the decade 2010-2019. Cattle contributed the most (60%) to the increase, followed by poultry (19%), pigs (15%), and sheep and goats (6%). Regionally, South Asia, Africa, and Latin America dominated the growth in global emissions since the 1990s. Nationally, the largest emissions were found in India (329 Gg N year-1), followed by China (267 Gg N year-1), the United States (163 Gg N year-1), Brazil (129 Gg N year-1) and Pakistan (102 Gg N year-1) in the 2010s. We found a substantial impact of livestock productivity, specifically animal body weight and milk yield, on the emission trends. Furthermore, a large spread existed among different methodologies in estimates of global N2O emission from livestock manure, with our results 20%-25% lower than those based on the 2006 IPCC Guidelines. This study highlights the need for robust time-variant model parameterization and continuous improvement of emissions factors to enhance the precision of emission inventories. Additionally, urgent mitigation is required, as all available inventories indicate a rapid increase in global N2O emissions from livestock manure in recent decades.

AGE-RELATED CHARACTERISTICS OF GLUTATHIONE-DEPENDENT ENZYMES FUNCTIONING IN RATS UNDER CONDITIONS OF TOXIC INJURY BY ACETAMINOPHEN

Aim. The study is dedicated to evaluating the enzymatic activities of the glutathione system in liver cells of rats from different age groups under conditions of toxic injury caused by acetaminophen. In the experiments, rats of two age categories were used: young (138–150 days) and mature age (348–360 days). Mehods. Acute toxic injury from acetaminophen was induced by administering it per os at a dose of 1250 mg/kg of animal body weight during the last two days of the experiment. Results. Under conditions of simulated acute toxic injury by the medicinal xenobiotic acetaminophen in the livers of young and mature rats, a decrease was observed in glutathione-S-transferase, Se-dependent glutathione peroxidase, and glutathione reductase activities. A significant decrease in non-Se-glutathione peroxidase in liver cells is observed only in mature animals that were administered toxic doses of acetaminophen. The influence of the age component can be considered as one of the critically important factors in suppressing the functional activity of the glutathione-dependent enzymatic system, manifested by decreased activity of glutathione-S-transferase, non-Se-glutathione peroxidase, Se-dependent glutathione peroxidase and glutathione reductase under conditions of toxic injury caused by the medicinal xenobiotic acetaminophen. A more pronounced decrease in glutathione-dependent enzymes under conditions of acetaminophen intoxication is observed in animals aged 360 days. Cunclusion. The consequence of the established changes could be the disruption of acetaminophen biotransformation in Phase II involving the glutathione system, which can be considered as one of the risk factors for the development of drug-induced hepatotoxicity in different age groups.

Study of Tildox AVZ effect on rat blood parameters in a subchronic experiment

The purpose of our research was to study the effect of Tildox AVZ on rat blood counts in a subchronic experiment. Tildox is a complex antibiotic in powder form. One gram of drug contains doxycycline hyclate – 100 mg and tylosin tartrate - 100 mg as active ingredients, sodium benzoate and sucrose as auxiliary substances. The experiment lasted 90 days. The study was conducted on 150 Wistar rats (75 males and 75 females). The body weight of the animals was 190-230 g. During the experiment 5 groups of 30 animals (15 males and 15 females) were formed, three of them were experimental groups, one - control and one – intact. Of the 150 rats involved in the experiment after its completion 100 individuals (50 males and 50 females) were killed for pathomorphological studies of internal organs.To identify the ability to recover and the appearance of resistance to toxic effects the remaining 50 animals (5 males and 5 females from each group) were monitored for 28 days after the experiment.An aqueous solution of the test sample of the drug was administered daily intragastrically using an atraumatic metal probe. The drug was administered to the first experimental group at a dose of 70 mg / kg, the second group - 265 mg / kg, the third group - at a dose of 1000 mg / kg of animal body weight. The control group was in equal conditions and received intragastric saline solution. Intact animals served as a reference. It was found that Tildox AVZ administered intragastrically at doses of 265 and 1000 mg / kg 1 time per day for 90 days has an effect on clinical and biochemical blood parameters. The drug administered at a dose of 70 mg / kg does not cause changes in blood parameters. However when examining the blood of rats 28 days after the recovery period there were no significant changes in clinical and biochemical parameters compared with the control and intact groups.From this it can be concluded that all blood changes had a dose-dependent effect and after stopping the use of the drug the body recovered which indicates the reversibility of the caused shifts in the blood picture.

Protective effects of Moringa oleifera against acetic acid-induced colitis in rat: Inflammatory mediators’ inhibition and preservation the colon morphohistology

Moringa oleifera decoction is used in folk medicine to alleviate various gastrointestinal ailments and has been shown in several studies to exhibit diverse biological activities: antioxidant, anti-inflammatory, and myorelaxant on intestine strips. However, its protective effect on pro-inflammatory cytokines in colitis remains to be ascertained. We investigated Moringa oleifera leaf aqueous extract activities on a rat model of acetic acid-induced colitis. Thirty-six rats were divided in random into six groups, and received either distilled water (10 mL/kg), the aqueous leaf extract of Moringa oleifera (25, 50, and 100 mg/kg) or the reference drug Loperamide (5 mg/kg) for 20 days. Animal body weight and food intake were followed-up. Colitis was induced on day 15, and daily stool weight was followed up. Animals were sacrificed (day 21), serum concentrations of pro-inflammatory cytokines MPO, IL-6, and TNF-α were evaluated, and the colon and liver preserved for histological examinations. After one-week pre-treatment, a significant (P < 0.05) weight increase was observed. At day 20, the extract significantly (P < 0.01) prevented weight loss. Food intake decreased by 36.33% in the colitis control, and by 4.34% in the extract (100 mg/kg) treated animals (P < 0.01). Moringa oleifera (100 mg/kg, day 20) decreased stool weights to 4.75±0.3 g (P < 0.05). The extract decreased (P < 0.01) MPO level. At 100 mg/kg, it significantly (P < 0.05) reduced IL-6 –0.58 ± 0.14 against 0.85 ± 0.00 ng/L in the colitis control. At the same dose, TNF-α levels decreased to 417.96 ± 0.17 ng/L (P < 0.001). Moringa oleifera alleviated colitis symptoms by reducing stool emission, alleviating inflammation, and preserving colon and liver cytoarchitecture.

Delivery of a telehealth supported home exercise program with dietary advice to increase plant-based protein in people with non-alcoholic fatty liver disease: a 12-week pilot feasibility randomised controlled trial

Telehealth overcomes common geographical barriers to community/clinic-based healthcare and lifestyle interventions, (1,2) but whether it is a feasible and safe mode of healthcare service delivery for lifestyle-based interventions in those with non-alcoholic fatty liver disease (NAFLD) remains unknown. This study evaluated the feasibility and safety of a home exercise program with dietary advice to increase plant-based protein delivered and monitored by healthcare professionals via telehealth in adults with NAFLD. Secondary aims were to assess changes in macronutrient intake including protein from plant and animal sources, body weight, physical activity and physical function. This was a 12-week pilot feasibility randomised controlled trial conducted in 28 inactive adults (&gt;45 years) with NAFLD. Participants were randomly allocated to receive: 1) a home-based, muscle strengthening exercise program (3 days/week) delivered and monitored remotely by an exercise physiologist using the TeleHab exercise platform/app (VALD Health) plus support from a nutritionist to increase daily protein intake to ~1.2-1.5 g/kg/day from predominately plant-based sources and behavioural change support delivered via 3-4 weekly text messages (Pro-Ex, n = 14) or 2) usual care (UC, n = 14). Feasibility was assessed via retention (defined as ≤10% attrition), adherence [≥66% to the muscle strengthening program and ≥80% to the recommended daily protein serves [total (≥3-3½), plant (≥2) and animal (≤1-1½) per day (via protein checklist)] and safety (intervention-related adverse events). Secondary outcomes included macronutrient intake (3x24-hour records), weight (self-reported), habitual physical activity (PA) [moderate-to-vigorous (MVPA), minutes/week via the Short International Physical Activity Questionnaire], and physical function [30-second sit-to-stand (STS) performance]. Since this was a pilot feasibility study, mean group differences (6 and 12-weeks) were estimated, with 95% confidence intervals, and standardised effects [Cohen D, effect size (ES)] reported for secondary outcomes. Overall, 25 participants (89%) completed the intervention. In Pro-Ex, mean adherence to the exercise program was 52%, while adherence to the recommended plant, animal and total protein serves/day was 32%, 42% and 14% of participants, respectively. One minor exercise-related adverse event occurred from 241 completed sessions over 12 weeks. Relative to UC, Pro-Ex experienced a mean 2.7 (95%CI: 0.9, 4.4; large ES d = 1.29) increase in 30-sec STS number, 46 minute (95%CI: −153, 245; small ES d = 0.19) increase in MVPA, 1.7kg (95%CI: −3.5, 0.2; moderate ES d = 0.54) decrease in body weight, 35.2g (95%CI: 11.0, 59.3; large ES d = 1.23) increase in protein and 8.3g (95%CI:-20.5, 4.0; moderate ES d=-0.57) reduction in saturated fat. In middle-aged and older adults with NAFLD, a home exercise and plant-based dietary protein intervention delivered via telehealth was safe, but not feasible in terms of achieving the desired level of adherence. Despite this, exploratory analysis indicates this mode of healthcare service delivery could play a role to support weight management and improve physical activity and physical function in adults with NAFLD.

Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.

Effect of Equisetum ramosissimum Desf. on body weight and Leptin/Ghrelin in standard and high-fat diet

The necessity of maintaining healthy habits, diet and minimal medical complications is challenging. The current study investigates Equisetum ramosissimum on levels of leptin, ghrelin, and their ratio in association with body weight changes in animals receiving standard and high-fat diet. Ethanolic extract was prepared by maceration and total phenols and flavonoids contents were determined using Folin-cicalto and AlCl3 methods. Study animals were fed with either standard or high-fat diets prior treatment with E. ramosissimum extract (500mg/kg). Body weights were monitored and serum concentrations of leptin, ghrelin and their ratios were determined. The plant extract comprised total phenols and flavonoids of 0.03 ± 0.01 mg/mg as Gallic acid, and 0.04 ± 0.03 mg/mg as quercetin, respectively. Findings revealed significant decrease in body weights of standard-diet animals and restoration of weight to normal after treatment with extract along with significant increase in serum ghrelin concentrations with strong correlation R and R2 values in respect to body weight. As well, significant reduction in serum leptin/ghrelin ratio was positively correlated with body weight and serum leptin levels. E. ramosissimum extract possessed promising characteristics on being introduced in dietary supplements and weight control regimens. The current study presented the influence of extract in decreasing body weight in animals fed with standard diet. Moreover, it restored the weights of obese animals which received the extract after gaining weight and being on high-fat diet. Further preclinical studies are warranted to reveal the translational potentials of E. ramosissimum extract and its vital effect on adipokines.

Morphological changes in the liver of bulls after the use of adaptogens

The paper presents the results of a study of the influence of adaptogens of plant and animal nature on the productive qualities of Kazakh white-headed bulls and morphological changes in their liver. 40 6-month-old beef bulls were selected for the study, which were divided into 4 groups: I (control) group of bulls consumed only the basic diet, II — adaptogen leucea safflower, III — drone homogenate, IV — pantocrine at the rate of 0.01 ml per 1 kg of animal body weight. At 18 months, a control slaughter of 3 animals from each group was carried out. During the experiment, it was found that the mass of the paired carcass in the bulls of the experimental groups increased by 11.1–21.7 kg (4.25–8.31%, р ≤ 0.05), the slaughter weight by 11.7–23.0 kg (4.24–8.34%, р ≤ 0.05–0.01), the slaughter yield by 0.9–1.9%. The analysis of the morphological composition of the carcass indicates an increase in the specific weight of its edible part of the carcass: by weight of muscle tissue by 4.0–7.7 kg (4.66–8.97%, р ≤ 0.05–0.01), fat — by 0.7–1.4 kg (4.67–9.33%, р ≤ 0.05). There is a high degree of maturity and high nutritional value of the meat of bulls of the experimental groups. Histological studies of the liver of bull calves indicate that when using tincture from drones, the liver structure corresponds to the norm, while in the control group animals some signs of dystrophic changes without pronounced infiltrations and signs of stagnation were found.

Abstract 1883: A MUC1 antibody-conjugated with a tubulysin B analog, DXC005, demonstrates excellent synergistic effect in combination with gemcitabine for treatment of pancreatic tumors

Abstract Pancreatic cancer is a malignant tumor with high incidence and mortality. It is difficult to diagnose and detect in the early stage, with low surgical resection rate and high recurrence and metastasis rate after surgery. At present, the clinical therapeutic strategy is extremely limited. The first-line Standard of Care (SOC) for unresectable pancreatic cancer is chemotherapy. The preferred regimen includes gemcitabine combined with albumin paclitaxel or FOLFIRINOX (5-FU+Oxaliplatin+Irinotecan). Due to the limited long-term benefits and toxic side effects of chemotherapy, targeted therapy combined with chemotherapy has become a new therapeutic strategy. MUC1 is a highly glycosylated transmembrane mucin located on the lumen surface of epithelial cells. It can protect cells from extreme factors and plays an important role in tumor cell metabolism, apoptosis, epithelial-mesenchymal transition (EMT) and metastasis. Previous studies have confirmed that MUC1 is highly expressed in a variety of tumors, including pancreatic cancer, and is closely related to poor prognosis. DXC005 is a novel MUC1-targeting antibody-drug conjugate (ADC), generated by conjugating a Tubulysin B analogue to a recombinant humanized anti-Muc1 monoclonal antibody. DXC005 is the first MUC1-ADC IND in China, and is currently in phase I clinical trials. Preclinical studies have confirmed the efficacy of DXC005 monotherapy (2.5 mg/kg, 5 mg/kg, 10 mg/kg in one administration) in the HuPrime ® pancreatic cancer PDX model (PA1194). The tumor growth inhibition (TGI) was 42.53 %, 70.77 %, and 95.58 %, respectively. We want to further clarify whether DXC005 combined with chemotherapeutic drug Gemcitabine can ensure or even improve the efficacy while reducing the dosage of Gemcitabine. In PA1194 xenograft model, DXC005 (3 mg/kg or 6 mg/kg) in combination with Gemcitabine (10 mg/kg) showed significant anti-tumor efficacy with 58.77% and 93.17% TGIs, respectively. In contrast, the treatment with 10 mg/kg of Gemcitabine alone exhibited much less TGI. Furthermore, complete response (CR) was observed in some animals after treatment with DXC005 (6 mg/kg) plus Gemcitabine (10 mg/kg). All groups of treatment are tolerated well, no abnormal animal behavior and body weight loss were observed in the study. The above results concluded that DXC005 combined with Gemcitabine can achieve synergistic effect even with reduced dose of Gemcitabine, which will serve as a support for synergistic application in clinical studies. Citation Format: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Yongxiang Chen, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Binbin Chen, Yanlei Yang, Meng Dai, Robert Y. Zhao. A MUC1 antibody-conjugated with a tubulysin B analog, DXC005, demonstrates excellent synergistic effect in combination with gemcitabine for treatment of pancreatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1883.

Abstract 478: Targeted combination nano-drug delivery system to enhance anti-cancer efficacy and reduce side effects

Abstract Background: Colorectal cancer (CRC) is a global health concern, with significant morbidity and mortality. Oxaliplatin (OXL) is a common treatment for CRC but its effectiveness is hampered by side effects, including gastrointestinal and neurotoxic effects. APX3330 exerts anti-angiogenic and neuroprotective effects. It is proposed that the combined use of OXL and APX3330-loaded nanoparticles (NPs) would improve drug delivery to cancer cells with enhanced therapeutic efficacy while reducing side effects of OXL. Methods: We developed dual-loaded NPs containing OXL and APX3330 linked to a cancer targeting monoclonal antibody (NPs+mAb). We characterized the physicochemical properties of the NPs and evaluated their cytotoxicity and drug release using CRC cell lines. In vivo, we assessed their therapeutic efficiency and side effects using an orthotopic CRC mouse model. Results: NPs exhibited an average size of 229±26 nm with a zeta potential of -24.1±2.1 mV. The drug loading and encapsulation efficiency were 3.3±0.2% and 71.9%, respectively. Morphological analysis via scanning electron microscopy confirmed NP structure. In vitro drug release studies showed a slower release profile from NPs compared to free OXL, with a cumulative release of 34% (w/w) after 48 hours. Notably, cytotoxicity evaluation on CT-26 cells revealed a significant reduction in the IC50 for NPs compared to free APX3330 and OXL. In vivo studies demonstrated a remarkable 31% reduction in tumor growth rate in animals treated with NPs+mAb compared to those receiving free forms of OXL and APX3330. Body weight for animals treated with NPs+mAb remained similar to the healthy group, indicating minimal systemic toxicity. Moreover, the length of the colon in healthy organs remained steady compared to animals treated with OXL, which experienced a reduction in colon length. Animals treated with the free form of OXL exhibited diarrhoea, while the stool water content for animals treated with NPs+mAb remained at a similar level as the healthy group, suggesting reduced gastrointestinal side effects. Conclusions: This study demonstrates the potential of NPs with improved retention and encapsulation efficiency for effective drug delivery. Our research validates our novel method for creating NPs with mAb conjugation, enhancing cytotoxicity against CRC cell lines. In conclusion, the designed NPs+mAb formulation improves OXL treatment efficacy, providing targeted delivery of anti-cancer drugs to the tumor site and reducing tumor size while minimizing side effects. Citation Format: Niloufar Rashidi, Majid Davidson, Vasso Apostolopoulos, Mark R. Kelley, Kulmira Nurgali. Targeted combination nano-drug delivery system to enhance anti-cancer efficacy and reduce side effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 478.

Abstract 4683: Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and &amp;gt; in situ

Abstract Introduction: Conophylline is an alkaloid isolated from the leaves of the Thai plant, Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions and an activator of pancreatic β-cell differentiation. It ameliorates various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and conophylline binds to the cytoplasmic portion of ARL6ip1. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. Previously, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and found that either deletion of ARL6ip1 or addition of conophylline inhibited migration, invasion and tumorigenicity in cultured cancer cells. In the present research we have studied the in vivo anticancer effect of conophylline and ARL6ip1 knockout, and the mechanism of anticancer activity in cultured cells. Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cell lines as human colorectal cancer cells. Cellular migration was measured by a wound-healing assay. The activity of Akt was measured by the phospho-Akt antibody. BALB/cSlc-nu/nu mice were used for the animal experiment. Results: Colon adenocarcinoma tissue microarray comparing tumor and adjacent normal tissues revealed that ARL6ip1 expression was significantly higher in cancer than in normal tissues. Intraperitoneal administration of conophylline and knockout of ARL6ip1 both inhibited the growth of HCT116 in mice. Neither influenced the bodyweight of animals. Conophylline and deletion of ARL6ip1 both inhibited the migration. Rescue of ARL6ip1 canceled the effect of ARL6ip1 deletion on migration in HCT116 and DLD1 cells. As the mechanism, either conophylline or ARL6ip1 knockout inhibited the Akt activity, which was canceled by the rescue of ARL6ip1 in both cell lines. Conclusion: ARL6ip1 was found to be highly expressed in the tumor tissue in colorectal cancer. CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline in the animal experiment. It is likely that the anticancer activity of conophylline would be mediated by Akt. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer. Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and &amp;gt; in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4683.

EVALUATION OF THE RELIABILITY AND CONCORDANCE OF VISUAL WEIGHT ASSESSMENT IN WATER BUFFALO FEMALES

&lt;p&gt;&lt;strong&gt;Background.&lt;/strong&gt; For the development of reproductive, nutritional and health programmes, estimation of animal body weight (BW) is a fundamental tool in herd management. &lt;strong&gt;Objective. &lt;/strong&gt;To evaluate of the reliability and concordance&lt;strong&gt; &lt;/strong&gt;of visual weight assessment in water buffalo females. &lt;strong&gt;Methodology. &lt;/strong&gt;Data on visually estimated body weight (VM) and actual body weight (BW) were recorded for 229 female water buffaloes. BW was recorded using a digital scale and visual estimation BW was taken as the average of three observations made by three observers. The measurements obtained by each of the different estimation methods were also compared with the observed weights by inspecting the paired Bland-Altman plots prior to logarithmic transformation. &lt;strong&gt;Results. &lt;/strong&gt;Correlations between observed BW and mean predicted BW for visual methods showed a positive and significant relationship (P&amp;lt;0.001), with an r value of 0.95. According to the intraclass correlation coefficient (ICC), there was a high degree of reliability in the visual estimates of buffalo weight, due to the similarity in the mean and dispersion of each observer's estimates. Both the Bland-Altman plot and the ICC show that there is a high level of concordance between the buffalo weights obtained by the visual and real methods. &lt;strong&gt;Implications.&lt;/strong&gt; The result of the present study showed that visual assessment highlights the ability of livestock handlers to have a very accurate estimation of BW in female water buffaloes. &lt;strong&gt;Conclusion.&lt;/strong&gt; The results of this study show that visual assessment highlights the ability of livestock handlers to visually estimate BW in female water buffaloes with high reliability and concordance with the animal weighbridge method.&lt;/p&gt;

Statistical tool for the estimation of body weight of lactating cows from 2D photographs

Estimating the body weights of animals is an arduous task in livestock management. However, it is a vital tool in developing suitable breeding programmes,calculating the nutritional requirements, determining pharmaceutical doses of drugs and assessing feed conversion efficiency and carcass quality. In this study, we made an attempt to predict the bodyweights of lactating cows using images from various angles. Seventeen lactating cows from the University Livestock Farm and Fodder Research Station, Mannuthy, were selected randomly. Different body measurements of the animals were obtained manually and photographs of the lateral, rear, and dorsal views were taken using the demo version of the CAD-KAS measure-pictures 1.0 software. The surface area was estimated using the body length along the back on the midline from the withers to the croup and the maximum stomach width from the dorsal view photographs. A stepwise multiple linear regression model was used to predict the body weight of the animals. A regression equation fitted using the surface area and perpendicular length between the Tail Head above and the plane in level with the ventral line of the abdomen below yielded an R2 of 90.5 percent. This study suggests that models built using measurements retrieved from digital image analysis techniques can be used as a promising tool for predicting the body weight of animals. Keywords: Cattle, body weight, digital image analysis, multiple linear regression

HIGH DOSES OF KETAMINE INFLICT MYOCARDIAL INJURY AND CAUSE CHANGES IN THE RELATIVE BODY WEIGHT TO HEART OF ADULT ALBINO WISTAR RATS

Objective: Ketamine is widely used as an anesthetic agent in surgery and emergency medicine. It is also used for procedural sedation, treatment of depression, pain management, and sometimes as a recreational drug. These uses, however, have recommended doses to prevent myocardial injury. This study, therefore, was designed to investigate the level of injury on the myocardium following the administration of high doses of ketamine and to determine the relative body weight to heart weight of the experimental animals. Method: A total of 12 male albino Wistar rats were used and grouped into four including the control group. They were weighed daily and administered 100 mg, 150 mg, and 200 mg/kg/body weight of ketamine intraperitoneally for 2 weeks and weighed again. Experiment was terminated after 14 days and animals were sacrificed and the heart harvested for analysis. Results: Ketamine caused a significant myocardial injury with increase in the doses in different groups by causing inflammation, hypertrophy, vacuolar degenerative changes, atrophy, and extensive hemorrhage around the myocytes. Weight differentiation was noticed in all experimental groups with heart weight contributing to the total body weight by 1.63%, 1.7%, and 1.2% for the 100 mg, 150 mg, and 200 mg/kg/body weight of ketamine groups, respectively. Conclusion: Higher doses of ketamine cause significant myocardial injury as well as differential changes in body weight and heart weight in experimental animals.

Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy

Background and aimsMesenchymal stromal cells (MSCs) a potentially effective disease-modulating therapy for diabetic nephropathy (DN) but their clinical translation has been hampered by incomplete understanding of the optimal timing of administration and in vivo mechanisms of action. This study aimed to elucidate the reno-protective potency and associated mechanisms of single intravenous injections of human umbilical cord-derived MSCs (hUC-MSCs) following shorter and longer durations of diabetes.MethodsA streptozotocin (STZ)-induced model of diabetes and DN was established in C57BL/6 mice. In groups of diabetic animals, human (h)UC-MSCs or vehicle were injected intravenously at 8 or 16 weeks after STZ along with vehicle-injected non-diabetic animals. Diabetes-related kidney abnormalities was analyzed 2 weeks later by urine and serum biochemical assays, histology, transmission electron microscopy and immunohistochemistry. Serum concentrations of pro-inflammatory and pro-fibrotic cytokines were quantified by ELISA. The expression of autophagy-related proteins within the renal cortices was investigated by immunoblotting. Bio-distribution of hUC-MSCs in kidney and other organs was evaluated in diabetic mice by injection of fluorescent-labelled cells.ResultsCompared to non-diabetic controls, diabetic mice had increases in urine albumin creatinine ratio (uACR), mesangial matrix deposition, podocyte foot process effacement, glomerular basement membrane thickening and interstitial fibrosis as well as reduced podocyte numbers at both 10 and 18 weeks after STZ. Early (8 weeks) hUC-MSC injection was associated with reduced uACR and improvements in multiple glomerular and renal interstitial abnormalities as well as reduced serum IL-6, TNF-α, and TGF-β1 compared to vehicle-injected animals. Later (16 weeks) hUC-MSC injection also resulted in reduction of diabetes-associated renal abnormalities and serum TGF-β1 but not of serum IL-6 and TNF-α. At both time-points, the kidneys of vehicle-injected diabetic mice had higher ratio of p-mTOR to mTOR, increased abundance of p62, lower abundance of ULK1 and Atg12, and reduced ratio of LC3B to LC3A compared to non-diabetic animals, consistent with diabetes-associated suppression of autophagy. These changes were largely reversed in the kidneys of hUC-MSC-injected mice. In contrast, neither early nor later hUC-MSC injection had effects on blood glucose and body weight of diabetic animals. Small numbers of CM-Dil-labeled hUC-MSCs remained detectable in kidneys, lungs and liver of diabetic mice at 14 days after intravenous injection.ConclusionsSingle intravenous injections of hUC-MSCs ameliorated glomerular abnormalities and interstitial fibrosis in a mouse model of STZ-induced diabetes without affecting hyperglycemia, whether administered at relatively short or longer duration of diabetes. At both time-points, the reno-protective effects of hUC-MSCs were associated with reduced circulating TGF-β1 and restoration of intra-renal autophagy.Graphical abstract

Body weight prediction in crossbred pigs from digital images using computer vision

The development of technologies made it possible to capture digital images by sensors in order to obtain morphometric measurements that can be used in the development of mathematical models for the prediction of body weight (BW) in animals. The objective was to develop mathematical models to predict body weight in crossbred pigs from morphometric measurements obtained with two-dimensional digital images. Data collection was carried out in the swine sector of IF Goiano, Urutai campus, in 52 crossbred pigs housed in the finishing phase. The animals were randomly weighed and filmed by the Microsoft Kinect® v1 sensor camera in the dorsal view. Subsequently, they were conducted for the measurement of manual morphometric measurements, without restraint, being dorsal length, chest width and flank width. The morphometric measurements predicted from the dorsal images were dorsal length, chest width, flank width, dorsal area and perimeter. Through Mask R-CNN algorithm trains the network by input images, was compute the area of the evaluated object in pixels, and thus, can correlate with measures of interest. The Mask R-CNN algorithm were performed with the Collaboratory Google using Phyton 3.0. Mathematical models were developed using multiple linear regression (MLR) and support vector regression (SVR) methodologies for body weight prediction. All Pearson's correlations between real body weight and real and predicted morphometric measurements by digital images were moderate to high magnitude positive and statistically significant (P<0.05). The difference between the real and predicted BW by the SVR was -1.74 kg (R² = 91%) and -2.39 kg (R² = 88%), respectively. The MLR model with real morphometrics measurements explained 60% of BW variance and estimated a BW 18.76 kg below from the real BW mean. The MLR model with predicted measurements explained 53% of BW variance and estimated a BW 22.51 kg below from the real BW mean. The mathematical model developed from SVR has the potential to estimate the body weight of crossbred pigs using morphometric measurements predicted by digital images such as dorsal length, width, dorsal area and perimeter.