The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased ob... more The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH–driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.
Constant improvements in nutrition and genetic selection over the last 20 years have led to a fas... more Constant improvements in nutrition and genetic selection over the last 20 years have led to a fast growth rates in modern broiler strains. Unfortunately this growth rate is also associated with increased body fat deposition, high mortality and high incidences of metabolic disease and skeletal disorders (Zubair and Lesson, 1996). These situations most commonly occur with broilers that consume feed ad libitum (Pasternak and Shalev, 1983). Feed restriction at an early stage of has been proposed to reduce some of these problems and even to have economical advantages (for example better feed conversion efficiency). However, the ability of broilers to fully recover in time is in dispute. The reason for such discrepancies could be mainly due to factors such as breed, initial body weight, sex and level of feed restriction. This experiment was conducted to evaluate the role of such factors as sex, initial body weight, breed and level of feeding on the compensatory growth of broiler chickens. The effect of three feeding levels (control, 15% and 30% below ad libitum), on male and female birds, at two initial body weights (light and heavy weight birds) and with two breeds (Ross and Aryan) on their subsequent growth performance was determined in a factorial statistical design experiment,. There were 4 replicates for each treatment and 5 birds in each replicate. The birds were restricted from 7 to 14 d of age and allowed ad libitum access until 49 d of age. One bird from each replicate of control group was killed at 49 d for carcaseanalysis. Male broilers not only had a significantly higher body weight, they had a better feed efficiency ratio and lower abdominal weight than female broilers (P < 0.05). Male broilers had also a better compensatory growth ability as judged by significantly higher growth rates (P < 0.05) than females. There were no differences between carcass components between males and females. The result showed that heavier birds (grouped at the start of the experimental period) have a greater (P < 0.05) total live weight by the end of compensatory growth period but they did not have a higher growth rate or better feed efficiency ratio. There were no significant differences in component parts of carcase and abdominal content between the two weight groups. Although the two breeds studied here had different growth patterns (Ross usually has an early fast growth while Aryan birds have a peak in growth at the end of experimental period) they both had similar overall growth performances. Birds with the higher restriction level had lower (P < 0.05) final body weights and feed intakes. There was no effect of restriction on feed efficiency ratio, abdominal fat content or carcase components.
Automatic identification and sorting of livestock organs in the meat processing industry could re... more Automatic identification and sorting of livestock organs in the meat processing industry could reduce costs and improve efficiency. Two hyperspectral sensors encompassing the visible (400–900 nm) and short-wave infrared (900–1700 nm) spectra were used to identify the organs by type. A total of 104 parenchymatous organs of cattle and sheep (heart, kidney, liver, and lung) were scanned in a multi-sensory system that encompassed both sensors along a conveyor belt. Spectral data were obtained and averaged following manual markup of three to eight regions of interest of each organ. Two methods were evaluated to classify organs: partial least squares discriminant analysis (PLS-DA) and random forest (RF). In addition, classification models were obtained with the smoothed reflectance and absorbance and the first and second derivatives of the spectra to assess if one was superior to the rest. The in-sample accuracy for the visible, short-wave infrared, and combination of both sensors was hig...
American Journal of Physiology-Gastrointestinal and Liver Physiology, 1989
The effects of canine gastric and pancreatic intrinsic factors on uptake and subcellular localiza... more The effects of canine gastric and pancreatic intrinsic factors on uptake and subcellular localization of cobalamin have been investigated in vivo to determine whether these proteins could mediate the physiological absorption of cobalamin in the dog. Cyano [57Co]cobalamin was introduced into ileal loops in dogs under general anesthesia, either free (control) or bound to gastric or pancreatic intrinsic factor. At 2 h, total uptake of cobalamin by ileal mucosa was significantly enhanced after prior binding to either gastric or pancreatic intrinsic factor compared with controls. Displacement of receptor-bound cobalamin with EDTA showed that enhanced total uptake reflected increased internalization of cobalamin by both proteins. Findings after reorienting sucrose density gradient centrifugation of ileal mucosa from loops containing intrinsic factor-cobalamin complexes were consistent with a major lysosomal and perhaps endosomal localization of internalized cobalamin, in agreement with re...
Acute phase proteins such as serum amyloid A, haptoglobin, and alpha 1-acid glycoprotein have bee... more Acute phase proteins such as serum amyloid A, haptoglobin, and alpha 1-acid glycoprotein have been identified as markers of inflammation in cattle because they are produced by the liver in response to pro-inflammatory cytokines. This study was designed to assess whether they could be used to discriminate between acute and chronic inflammation. Their concentrations were measured in serum samples from 81 cattle in which inflammation was classified by thorough clinical examination, supported by postmortem findings, as being acute in severity in 31 and chronic in 50. The classical haematological markers of inflammation were also determined in blood from the animals. Serum amyloid A had a maximum (100 per cent) clinical sensitivity in discriminating between the acute and chronic cases, and haptoglobin had the highest clinical specificity of 76 per cent; counts of neutrophils and band neutrophils had sensitivities of 71 per cent and 42 per cent and specificities of 30 per cent and 72 per cent, respectively. It was concluded that serum amyloid A and haptoglobin may be used to discriminate between acute and chronic inflammatory conditions.
The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased ob... more The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH–driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.
Constant improvements in nutrition and genetic selection over the last 20 years have led to a fas... more Constant improvements in nutrition and genetic selection over the last 20 years have led to a fast growth rates in modern broiler strains. Unfortunately this growth rate is also associated with increased body fat deposition, high mortality and high incidences of metabolic disease and skeletal disorders (Zubair and Lesson, 1996). These situations most commonly occur with broilers that consume feed ad libitum (Pasternak and Shalev, 1983). Feed restriction at an early stage of has been proposed to reduce some of these problems and even to have economical advantages (for example better feed conversion efficiency). However, the ability of broilers to fully recover in time is in dispute. The reason for such discrepancies could be mainly due to factors such as breed, initial body weight, sex and level of feed restriction. This experiment was conducted to evaluate the role of such factors as sex, initial body weight, breed and level of feeding on the compensatory growth of broiler chickens. The effect of three feeding levels (control, 15% and 30% below ad libitum), on male and female birds, at two initial body weights (light and heavy weight birds) and with two breeds (Ross and Aryan) on their subsequent growth performance was determined in a factorial statistical design experiment,. There were 4 replicates for each treatment and 5 birds in each replicate. The birds were restricted from 7 to 14 d of age and allowed ad libitum access until 49 d of age. One bird from each replicate of control group was killed at 49 d for carcaseanalysis. Male broilers not only had a significantly higher body weight, they had a better feed efficiency ratio and lower abdominal weight than female broilers (P < 0.05). Male broilers had also a better compensatory growth ability as judged by significantly higher growth rates (P < 0.05) than females. There were no differences between carcass components between males and females. The result showed that heavier birds (grouped at the start of the experimental period) have a greater (P < 0.05) total live weight by the end of compensatory growth period but they did not have a higher growth rate or better feed efficiency ratio. There were no significant differences in component parts of carcase and abdominal content between the two weight groups. Although the two breeds studied here had different growth patterns (Ross usually has an early fast growth while Aryan birds have a peak in growth at the end of experimental period) they both had similar overall growth performances. Birds with the higher restriction level had lower (P < 0.05) final body weights and feed intakes. There was no effect of restriction on feed efficiency ratio, abdominal fat content or carcase components.
Automatic identification and sorting of livestock organs in the meat processing industry could re... more Automatic identification and sorting of livestock organs in the meat processing industry could reduce costs and improve efficiency. Two hyperspectral sensors encompassing the visible (400–900 nm) and short-wave infrared (900–1700 nm) spectra were used to identify the organs by type. A total of 104 parenchymatous organs of cattle and sheep (heart, kidney, liver, and lung) were scanned in a multi-sensory system that encompassed both sensors along a conveyor belt. Spectral data were obtained and averaged following manual markup of three to eight regions of interest of each organ. Two methods were evaluated to classify organs: partial least squares discriminant analysis (PLS-DA) and random forest (RF). In addition, classification models were obtained with the smoothed reflectance and absorbance and the first and second derivatives of the spectra to assess if one was superior to the rest. The in-sample accuracy for the visible, short-wave infrared, and combination of both sensors was hig...
American Journal of Physiology-Gastrointestinal and Liver Physiology, 1989
The effects of canine gastric and pancreatic intrinsic factors on uptake and subcellular localiza... more The effects of canine gastric and pancreatic intrinsic factors on uptake and subcellular localization of cobalamin have been investigated in vivo to determine whether these proteins could mediate the physiological absorption of cobalamin in the dog. Cyano [57Co]cobalamin was introduced into ileal loops in dogs under general anesthesia, either free (control) or bound to gastric or pancreatic intrinsic factor. At 2 h, total uptake of cobalamin by ileal mucosa was significantly enhanced after prior binding to either gastric or pancreatic intrinsic factor compared with controls. Displacement of receptor-bound cobalamin with EDTA showed that enhanced total uptake reflected increased internalization of cobalamin by both proteins. Findings after reorienting sucrose density gradient centrifugation of ileal mucosa from loops containing intrinsic factor-cobalamin complexes were consistent with a major lysosomal and perhaps endosomal localization of internalized cobalamin, in agreement with re...
Acute phase proteins such as serum amyloid A, haptoglobin, and alpha 1-acid glycoprotein have bee... more Acute phase proteins such as serum amyloid A, haptoglobin, and alpha 1-acid glycoprotein have been identified as markers of inflammation in cattle because they are produced by the liver in response to pro-inflammatory cytokines. This study was designed to assess whether they could be used to discriminate between acute and chronic inflammation. Their concentrations were measured in serum samples from 81 cattle in which inflammation was classified by thorough clinical examination, supported by postmortem findings, as being acute in severity in 31 and chronic in 50. The classical haematological markers of inflammation were also determined in blood from the animals. Serum amyloid A had a maximum (100 per cent) clinical sensitivity in discriminating between the acute and chronic cases, and haptoglobin had the highest clinical specificity of 76 per cent; counts of neutrophils and band neutrophils had sensitivities of 71 per cent and 42 per cent and specificities of 30 per cent and 72 per cent, respectively. It was concluded that serum amyloid A and haptoglobin may be used to discriminate between acute and chronic inflammatory conditions.
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Papers by Neil Horadagoda