Polydextrose studies in relation to lipid metabolism done in animals.
\r\n\tThis book aims to expose the recent advances in the research and development of chemical and biochemical processes to obtain bio-based chemical compounds and fuels from glycerol.
\r\n\r\n\tChapters dealing with the synthesis and characterization of catalysts (single and mixed hydroxides and oxides, supported catalysts, zeolites, heteropolyacids, pillared-clays, and metal-organic frameworks) and biocatalysts (novel microbial and fungi cultures, immobilized cells, immobilized enzymes, and nanobiocatalysts) to carry out the conversion of glycerol, as well as their testing in discontinuous and continuous stirred reactors, fixed-bed, fluidized-bed, trickle-bed, bubble column, airlift and membrane (bio)reactors are welcome.
\r\n\r\n\tThe book will comprise, but will not be limited to, the homogeneous and heterogeneous chemical reactions of glycerol such as dehydration, hydrogenolysis, partial oxidation, steam- and dry-reforming, glycerol to hydrocarbon fuels and aromatics, (trans)esterification, etherification, halogenation, ammoxidation, as well as supercritical, and photocatalytic processes.
\r\n\r\n\tAdditionally, we hope to cover the bioprocessing of glycerol, including microbial and fungal fermentation and enzymatic reactions to obtain C2-C4 alcohols, diols, hydrogen, methane, organic acids, dihydroxyacetone, biopolymers, and others.
\r\n\tThe book will also deal with the engineering aspects of glycerol processing, such as chemical equilibrium of glycerol reactions, reaction kinetics, (bio)reactor modeling, as well as process simulation and optimization of process variables and reactors.
Dietary fiber include fibers from natural sources (such as fruits, vegetables, and wholegrain cereals), fibers that are extracted or obtained by other means from food material, and synthetic carbohydrate polymers, that have been shown to possess physiological health benefits [1, 2]. Dietary fiber can be classified analytically as soluble and insoluble based on their solubility in water, but can also be characterized as viscous or non-viscous and fermentable or non-fermentable depending upon the physiological characteristics the fiber might have [2]. Insoluble dietary fiber includes cellulose, part of hemicellulose, and lignin, whereas soluble fibers include components such as pectin, some hemicelluloses, lignin, gums and mucilage [2, 3]. Whilst there have been difficulties in achieving a global definition for dietary fiber, it is now generally accepted that dietary fiber can be defined as carbohydrate polymers with a degree of polymerization of 3 or more monomeric units which are not hydrolysed in the small intestine by the endogenous enzymes [4]. As fiber is resistant to digestion and absorption in the human small intestine, it enters the colon where it can be partially or completely fermented [5].
Polydextrose is a polysaccharide produced by the random polymerization of glucose in the presence of sorbitol and a suitable acid catalyst, at a high temperature and under partial vacuum [6]. Polydextrose is composed of a mixture of glucose oligomers, with an average degree of polymerization ~12, but ranging from residual monomer to dp >100 [6, 7]. It is a branched molecule, and contains all different combinations of α- and β-linked 1→2, 1→3, 1→4 and 1→6 glycosidic linkages (Figure 1) [7, 8]. As polydextrose is only partially digested during gastrointestinal transit, it acts as a substrate for saccharolytic fermentation throughout the colon, even to the distal parts [9-12]. Polydextrose has a low caloric value: about 1 kcal/g, and it is widely used as a bulking agent and to replace the structure and texture of sucrose in low-calorie products by the food industry in confectionery applications, in pastry and bread, in dairy products, meat products, pasta and noodles, and in beverages [7, 13]. Polydextrose is widely accepted as a soluble fiber and has scientifically substantiated fiber characteristics, including increase in stool weight, decreased transit time, improved stool consistency and ease of defecation, and reduced fecal pH [7]. It is safe to use, and well tolerated, with a mean laxative threshold of 90 g/day, or 50 g as a single bolus dose [14-16].
Structure for the polydextrose. The letter R can be either hydrogen (H), sorbitol, sorbitol bridge, of more polydextrose. Polydextrose has highly branched complex three-dimensional structure with all different combinations of α- and β-linked 1→2, 1→3, 1→4 and 1→6 glycosidic linkages.
Several beneficial effects have been linked to the consumption of polydextrose. Consumption of polydextrose promotes the growth of beneficial bifidobacteria and lactobacilli while preventing the growth of harmful ones, such as clostridia [17, 18]. It has been suggested to possess anti-inflammatory actions and to improve the signs of osteoarthritis in canines [19], to increase IgA amount in the rat cecum [20], to reduce cyclo-oxygenase 2 expression in pigs distal colon, and to reduce lesions in rat colitis model [21]. Furthermore, it has been suggested to improve the absorption of magnesium, calcium [22-25] and iron [26].
Soluble fiber, both viscous (e.g. gums, pectin and β-glucan) and non-viscous (e.g. polydextrose, resistant maltodextrin and inulin), has been suggested to have beneficial metabolic advantages. These include increasing satiety and reduction of body weight, control of postprandial glycemic and insulin responses, and hypocholesterolemic effects on serum lipid parameters [5, 27]. The inverse relationship of higher HDL to coronary artery disease risk has been recognized and is evident across numerous populations, and the increment of its relative amount over LDL has been generally accepted as a hallmark of better cardiovascular health [28]. Soluble fiber has been associated inversely with serum total and LDL cholesterol, while HDL cholesterol concentration has been reported to either slightly decrease or remain unchanged [29, 30]. This effect has been attributed as an effect of soluble viscous fibers, as insoluble fibers do not appear to affect serum cholesterol concentrations [31, 32]. The ability of soluble fibers to reduce serum triglyceride levels is also controversial, as in some studies an inverse association has been suggested, while in many studies no effect has been observed [29, 33]. Soluble viscous fibers have a characteristic of being hypocholesterolemic, reducing serum cholesterol by about 5-10 % for a 5-10 g dose in subjects with hypercholesterolemia, whereas insoluble fibers have not shown this effect [34].
Polydextrose is a fermentable non-viscous fiber, and has been shown to exhibit lipid metabolism regulating effects [5]. Typically these effects have been associated with two physiochemical properties of soluble fibers: viscosity and fermentability. Viscous soluble fibers may work by slowing down gastric emptying and prevention of bile salt re-absorption which would increase the secretion of bile acids and neutral sterols into feces and interruption of the enterohepatic circulation of bile acids [35, 36]. Soluble fiber can also decrease intestinal cholesterol absorption by affecting micelle formation and mobility [37, 38], and reduce glycemic response leading to lower insulin stimulation and hepatic cholesterol synthesis [39]. Fibers can also promote satiety [40]. Additionally, colonic fermentation products of these fibers, short chain fatty acids (SCFAs), mainly propionate, have been shown to inhibit hepatic fatty acid synthesis [41]. Polydextrose has been reported to confer lipid modulating effects in human clinical intervention studies, as well as in animal studies. However, some of the characteristics of polydextrose are different to other soluble fibers, such as low viscosity, and sustained fermentation throughout the colon [11].
The ability of polydextrose to modulate triglycerides, total, LDL, and HDL cholesterol has been studied in animals both in normal diets without additional lipid load or in diets in which lipids have been included as part of the normal diet. There is a clear difference between the types of studies, as the two studies without lipid load have not shown any effect on the blood lipid values. In a 6-week feeding study in normal rats with 5 % (w/w) inclusion of polydextrose no change in plasma triglycerides, total cholesterol, and HDL cholesterol or liver cholesterol, triglycerides and phospholipids was observed [42]. Another, 15-day feeding trial with rats, did not show differences in serum total and free cholesterol, triacylglycerols, and phospholipids even though 3 % polydextrose was administered together with 3 % pectin or 3 % cellulose [43].
However, in two other rat feeding studies in which polydextrose was accompanied with a lipid load, reduced lipid levels were reported. In one study rats were given two different dosages of corn oil, 10 % and 20 %, to represent a moderate or high fat diet, for 8 weeks, with or without 5 % polydextrose [44]. Rats in the polydextrose group showed decreased serum triglycerides as compared to a guar gum control in the high-fat diet, and increased levels of serum HDL cholesterol both in the moderate fat and high fat diet [44]. Serum total lipids and cholesterol remained at the level of the control [44]. One study has been done with gerbils: in the 4-week study the gerbils were fed with 0.15 % cholesterol with 30 % of the energy coming from fat and with inclusion of 6 % polydextrose [45]. Both liver and plasma total cholesterol as well as free and esterified cholesterol from liver decreased in the polydextrose group [45]. The effect was presumed by the authors to be related to the reduction of VLDL and LDL, since no change in HDL was observed [45]. In the same gerbil study, it was additionally investigated whether polydextrose can remove cholesterol from
Polydextrose studies in relation to lipid metabolism done in animals.
endogenous pools by first artificially expanding the endogenous cholesterol pools of the gerbils with a preload of 0.4 % cholesterol for two weeks before 6 % polydextrose was fed for an additional three weeks. Polydextrose was shown to hasten the endogenous clearance of cholesterol pools, and to reduce liver and plasma total cholesterol, esterified cholesterol from liver and plasma HDL cholesterol [45].
The acute response of polydextrose on serum lipid values has also been studied in rats, but together with lactitol [46]. Polydextrose was administered as a 28 % solution in a dose of 3 ml/200 g of body weight in a solution also containing 26 % lactitol and a fat emulsion which was comparable to one in chocolate. The rats showed reduced serum triglyceride levels, and an increase in luminal triglyceride levels in the cecum after 150 minutes of ingestion of polydextrose, which would indicate that the combination of polydextrose and lactitol reduced either the level of fat absorption in the earlier part of small intestine or promoted the transit time of fat through the intestine [46]. No change in total, HDL, or LDL cholesterol were found in that study.
These studies are summarised in Table 1. There is an indication from these studies that polydextrose can lower total cholesterol and has a tendency to lower LDL cholesterol and tendency to increase HDL cholesterol.
Clinical intervention studies with polydextrose have been conducted either with healthy adults, with individuals having hypercholesterolemia or with individuals with impaired glucose tolerance.
In a human study with normal healthy adults with no reported hypercholesterolemia a reduction in the amount of total HDL by administration of 15 g of polydextrose for two months with concomitant decrease in apolipoprotein A-I, which is the main component of the HDL cholesterol, has been observed [47]. Apolipoprotein B levels, found in all atherogenic apolipoprotein particles, and the LDL cholesterol levels itself had also a tendency to be reduced after the 2-month and 1-month intervention period, respectively [47]. In another study with healthy adults, administration of 10 g of polydextrose for 18 days was shown to decrease LDL cholesterol and total cholesterol values with no effect on HDL cholesterol or triglycerides [48]. There are also contradictory results with healthy humans, as administration of polydextrose in an amount from 4 to 12 g per day for 29 days did not affect triacylglycerol, or cholesterol [49]. However, in that study no data was shown, and in addition to which the cholesterol type measured was not specified.
In hypercholesterolomic individuals, the effect of polydextrose has been studied in a 4-week study with administration of 15 g and 30 g polydextrose daily [45]. The study was quite small, with only 12 subjects participating, and each individual subject serving as a control for him/herself. In this study it was noted that 5 of the 6 individuals ingesting 30 g of polydextrose were in a separate responder group, and in this group the LDL cholesterol values declined significantly, and there was a tendency for reduced total cholesterol, but no change in HDL cholesterol. However, when all 6 individuals were studied together, no change compared to control was observed.
In diabetic patients, diets containing high amounts of fiber have improved plasma lipid control [50, 51]. The effect of polydextrose on lipid values has been of interest in two studies with individuals showing abnormal glucose metabolism or type 2 diabetes. In subjects with impaired glucose metabolism, polydextrose administered for 12 weeks at 16 g/day has been observed to lower LDL cholesterol, increase HDL cholesterol and cause no change in triglycerides [52]. In this study, LDL cholesterol decreased also in the control group probably because of simultaneous nutrition consultation by a nutritionist [52]. In a combination study with 7 g polydextrose and 3 g oligofructose administered daily for 6 weeks in adults with type 2 diabetes, a decrease in total cholesterol, triglycerides, VLDL cholesterol, and ratios of total cholesterol to HDL cholesterol, and LDL cholesterol to HDL cholesterol was observed, while HDL cholesterol increased [53].
The acute effect of polydextrose has been studied in humans too, together with lactitol, in the triglyceride levels after consumption of 46 g of chocolate supplemented with 15.1 % of the weight with polydextrose. The intervention group had reduced serum triglycerides in comparison to control chocolate during the 150 minutes the triglycerides were measured from the blood [46]. During intense exercise, polydextrose has been shown to reduce the amount of free fatty acids in plasma [54]. In addition, an abstract has been published about ingestion of 12.5 g polydextrose during a hamburger meal observing a reduction in total postprandial hypertriglyceridemia by 25 % [55].
HDL is highly heterogeneous, and subfractions of it can be identified on the basis of density, size, charge, and protein composition [56]. Different fractions of HDL can be identified by ultracentrifugation, gradient gel electrophoresis, and nuclear magnetic resonance (NMR) spectroscopy, and these different fractions could play diverse roles in protective function [56, 57]. It is thought that certain fractions of HDL cholesterol could be better predictors of cardiovascular diseases and its risk. However, controversy about the role of the different forms still exists, as in [58] and in [59] increased HDL2 and apoA-I levels were associated as protective against coronary heart disease. In other studies, in turn, such as in [60], and [61], the HDL3 has had a stronger inverse association with coronary heart disease. The early studies, however, more strongly indicate that reduced levels of HDL2 over HDL3 is associated more strongly to CVD risk [62].
The different subfractions of HDL and the impact of ingestion of polydextrose on their distribution has been investigated in one study [47], and in this study HDL3 was increased during the 2-month intervention period and one month after finishing the study. At the same time, a reduced level of HDL2, apoA-I and LCAT activity was observed. In other studies with soluble fibers, such as with guar gum, no changes in HDL2 and HDL3 subfractions or their ratio were observed [63, 64]. No difference between serum HDL2 and HDL3 cholesterol subfractions could be observed between high-fiber, consisting partially of soluble fiber from psyllium, and low-fiber diets [65] or with beta-glucan as an oat fiber extract [66]. In addition, lack of standardization among the analytical methods that are used to measure size distribution of different HDL2 and HDL3 subfractions may cause approximation of HDL subclass levels [67, 68].
Polydextrose clinical intervention studies in which lipid values have been measured.
Table 2 summarizes the different human clinical intervention studies done with polydextrose in relation to HDL, LDL, total cholesterol and triglycerides. From these studies it can be concluded that polydextrose in the diet can lower serum total and LDL cholesterol and triglycerides. There are two studies in which definite increases in HDL have been observed.
One of the mechanisms by which soluble viscous fibers induce hypocholesterolemic responses is the disruption of enterohepatic bile acid circulation, which reduces absorption of intestinal bile acids. The major route by which cholesterol in the liver is eliminated is through the de novo synthesis of primary bile acids from cholesterol [70]. The bile is released into the small intestine, where bile salt micelles help in the solubilisation of lipophilic components, such as cholesterol, fat soluble vitamins, and other lipids [70]. The diffusion of the micelles with solubilised components as well as the biliary and dietary cholesterol across the unstirred water layer, covering the luminal side of the enterocytes facilitate the uptake of cholesterol and other lipophilic components by the enterocytes [71]. When the bile salt micelles have accomplished their role they transit the remainder of small and large intestine where they are progressively absorbed into the enterohepatic circulation by the hepatic portal vein [70]. The bile salts that escape the intestinal absorption are transformed through colonic bacterial enzymatic activity to form secondary bile salts, from which deoxycholic acid is absorbed passively through colonic epithelium into the enterohepatic circulation, while lithocholic acid is secreted into the feces [72]. The amount of bile salts, both primary and secondary, is maintained in a rather constant level, and the daily bile salt losses are compensated by de novo hepatic biosynthesis [73]. The enterohepatic circulation is very efficient, as 95 % of the bile salts released into the intestine is absorbed back to the liver [70].
The presence of viscous soluble fiber has been shown to prevent bile salt reabsorption, which leads to enhanced excretion of bile salts into feces [35, 36]. This depletes the bile acids from liver and leads to rapid catabolisation of cholesterol through activation of 7alpha-hydroxylase. At the same time cholesteryl esters are metabolised, and in order to replace these production of LDL surface membrane receptors and concomitant LDL cholesterol uptake from blood stream are increased. This leads to lowering of the blood cholesterol concentration [74]. The fibers presumably interact with bile acids directly at the molecular level or entrap bile salt micelles in the gelatinous network formed by the polymeric fiber [35, 75]. The fiber can also form a barrier which can prevent the formation of bile acid micelles, and increase the unstirred water layer lining the intestinal mucosal surface [76].
Polydextrose is a non-viscous fiber and its capacity to bind bile salts has been studied in one clinical intervention study [77]. In this study, administration of polydextrose in healthy adults at 8 g/day for three weeks was not found to increase fecal excretion of total bile acids and secondary bile acids, but rather decreased values were observed during the intervention period compared to the run-in period before [77]. A similar observation was made in normal rats, in which administration of 5 % polydextrose for 6 weeks did not increase the fecal output of bile acids [42]. The low ability of polydextrose to bind bile acids is not, however, surprising. In order for a fiber to bind bile acids, it is required to be viscous in nature, and polydextrose is lower in viscosity for instance in comparison to pectin and guar gum which have high water binding capacity with higher viscosity and thus increased capability to bind bile acids [42, 78]. Polydextrose has a high capacity to bind water, and it can for instance relieve constipation presumably due to this characteristic, but there is no gel formation by polydextrose in water and little viscosity [43, 79, 80].
Even though no clear effect on bile acid binding can be detected, the fact that cholesterol and triglyceride absorption can still be modulated, are indications that polydextrose can retard the transportation of lipids from the intestinal lumen to the lymph. When polydextrose was infused as 5 % and 10 % to duodenum together with cholesterol and triglyceride on mesenteric lymph-fistulated rats, the amount of cholesterol and triglycerides in the lymph decreased dose-dependently, and concomitantly the amount of the unabsorbed lipids increased in the lumen of the intestine [81]. It was concluded that since most of the luminal triglyceride and cholesterol was detected in the proximal part of the small intestine, the absorption of the lipids was inhibited. There was a tendency to have increased amount of cholesterol and a significant increase of triglycerides remaining in the colon which could indicate that some of the lipids were not absorbed [81]. However, polydextrose did not seem to increase secretion of cholesterol into feces in rats even though some tendency was observed in another study [82].
In an acute response study of polydextrose in combination with lactitol in rats with lipid load similar to the composition of chocolate an increase in luminal triglyceride in the cecum was observed with concomitant decrease in serum triglycerides [46]. This would indicate that the combination of polydextrose and lactitol reduced either the level of fat absorption in the earlier part of small intestine or promoted the transit time of fat through the intestine [46].
Cholesterol that escapes absorption is partially degraded to coprostanol and coprostanone by colon microbes [83]. A decrease of the degradation products coprostanol, coprostanon and cholestanol has been observed [77] which would indicate that the amount of cholesterol entering the colon is less in humans receiving polydextrose.
When soluble fiber enters the large intestine, it is fermented by the residual microbes forming short-chain fatty acids (SCFAs), butyrate, acetate, and propionate, end-products of bacterial carbohydrate fermentation. The SCFAs have been indicated to possess different physiological functions. Butyrate has been implicated to be the most important SCFA for colonic and immune cells due to its ability to serve as energy source for colonic epithelium as well as regulate cell growth and differentiation [84, 85]. It is a preferred energy source by colonocytes over glucose, glutamine, or other SCFA, and 70 to 90 % of butyrate is metabolized by colonocytes [86]. It has been implicated to inhibit intestinal cholesterol biosynthesis [87]. Acetate, as a direct substrate for acetyl-CoA synthetase, an enzyme that converts acetate to acetyl-CoA for entering to the cholesterol and fatty acid synthesis cycle, has been implicated to increase liver cholesterol, and fatty acid levels [41, 88]. Acetate has been shown to associate negatively with visceral adipose tissues and insulin levels in obese people [89]. Propionate has been shown to possess antilipogenic and cholesterol-lowering effects. While acetate is a substrate for sterol and fatty acid synthesis, propionate counteracts this by inhibiting acetate incorporation to serum lipids [41]. Propionate has been shown to to reduce the rate of cholesterol synthesis [87, 90], to inhibit fatty acid synthesis [91], to decrease liver lipogenesis [92], and to decrease hepatic and plasma and serum cholesterol levels [93, 94]. Propionate supplementation has been shown increase serum HDL cholesterol and triglyceride levels without effect on total cholesterol [92, 95]. However, contradictory results about its efficacy on cholesterol metabolism has been also observed [96-98].
The production of short-chain fatty acids during polydextrose fermentation has been studied with batch fermentations, colon simulators as well as from feces in animal and human studies. The differences in the results reflect individual variation, sampling, and differences in the methods used. Fecal SCFA concentration measurements are not the best indicators of SCFA produced as the majority of fecal SCFA is absorbed rapidly by the colonic epithelial cells [99]. Polydextrose has been observed to increase the production of butyrate, acetate and propionate in vitro [18, 100-102], in rats [20], pigs [11], in dogs [103] and in humans [17, 49]. When compared to other fibers, polydextrose produced similar quantities of SCFAs, and the molecular ratio of acetate/propionate/butyrate produced was found to be similar to that of fructo-oligosaccharides and xylo-oligosaccharides and other carbohydrates, such as inulin, pectin, and arabinose [104, 105] while in other studies polydextrose produced less total SCFAs compared to FOS, inulin and GOS [102, 106, 107]. The lower production of SCFAs by polydextrose can be explained by the lower digestability of polydextrose and its more sustained fermentation throughout the gut due to its branched complex structure. Furthermore, polydextrose fermentation has been shown to reduce putrefactive microbial metabolites, or branched-chain fatty acids and biogenic amines produced from protein fermentation [11, 20, 49, 100, 101, 107-109] but the decrease of these in relation to lipid metabolism and absorption is unknown. Figure 2 shows an example of how fermentation of polydextrose increases the amount short chain fatty acids in an in vitro colon simulation both when the amount of polydextrose is increased, and when the simulation proceeds from vessel V1 representing proximal part of the colon towards the vessels representing more distal parts of the colon [108].
Concentration (mM) of short chain fatty acids (SCFAs) in the different vessels V1, V2, V3, and V4 after 48h in vitro colon fermentation simulation. An increase in the concentration of SCFAs can be observed both dose-dependently as well as from vessels representing proximal colon V1 towards vessels representing more distal parts of the colon, V3 and V4.
When polydextrose enters the colon, it is fermented by the indigenous microbiota, thus serving as an energy-source to promote their growth and survival. In germ-free mice, the transplantation of the colonic microbiota from normal mice resulted in a 60 % increase in body fat in an unchanged diet [110] and there are an increasing number of reports that the gut microbiota may play an important role in cholesterol and lipid homeostasis, in obesity and metabolic syndrome [111-113].
Bacterial DNA of fecal samples from 20 individuals consuming 21 g of polydextrose in 3 doses per day were pyrosequenced, and the amount of Clostridiaceae, and Veillonea increased while Lachnospiraeae and Eubacteriaceae decreased compared to the control group without additional supplemental fiber [114]. Well-known butyrate-producers were increased in number, such as Faecalibacterium, and especially Faecalibacterium prausnitzii, whereas other SCFA producers, such as Lachnospiraceae, and Eubacteriaceae were reduced in number by administration of polydextrose [114]. Polydextrose also decreased the number of Coriobacteriaceae, which have been shown to have a positive association to non-HDL cholesterol [111, 114]. Interestingly, bifidobacteria have shown a positive correlation with HDL-cholesterol [111], but the bifidobacterial counts were decreased by polydextrose when studied with pyrosequencing [114]. In other studies polydextrose administration has been shown to increase the amount of bifidobacteria and lactobacilli [17, 18, 49, 106, 107, 115] while in some studies this effect has not been noted [103] or that there was no effect on the growth of lactobacilli [102]. This kind of inconsistency in the response could reflect the interindividual differences in indigenous microbiota to begin with. These kind of fluctuations in the indigenous microbiota, however, might explain why there are differencies in the studies with polydextrose and its effect on cholesterol values, for instance in [45] in which a responder group with a decrease in LDL was observed.
Fibers can affect blood glucose levels by decreasing the glycemic load of a meal or by affecting glucose absorption or release of glucose [5], and especially soluble fiber has been shown to attenuate the absorption of glucose [27]. Soluble dietary fibers may affect total and LDL cholesterol levels through effects on postprandial glycemia, as reduction in the glucose absorption, which would lower the insulin level and its production in the pancreas, would then lead to a decrease in cholesterol synthesis [116]. When soluble dietary fibers are being digested they delay the emptying of digested food from the stomach to the small intestine, slow down the transportation and mixing of digestive enzymes in the chyme and increase the resistance of the unstirred water layer lining the mucosa [117, 118]. This leads to reduction in the absorption of glucose and macronutrients, and lowered level of postprandial glucose is accompanied with lowered insulin level which would possibly lead to lowered hepatic cholesterol synthesis. [39]. There has been studies describing inverse relationship between glycemic load and HDL cholesterol [119, 120], and an indirect regulation of intestinal lipid uptake by dietary glucose has been presumed. Short-term incubation with intestinal epithelial cells, Caco-2 cells, with glucose on the apical side induces a significant uptake of cholesterol in a dose-dependent manner [121], and in addition cholesterol synthesis seems to dependent on glucose intake [122].
The effect of polydextrose ingestion on glucose and postprandial insulin response has been investigated in several studies. Polydextrose has a very low glycemic index (4 to 7) with glycemic load of 1 compared to the reference glucose (100) [7, 123]. Polydextrose has been reported to attenuate the blood glucose raising potential of glucose, as the glycemic index of glucose was reduced from 100 to 88 when 12 grams of polydextrose was ingested together with glucose by healthy adults [49]. Similar results were observed in a study with healthy adults when 14 g was ingested together with 50 g of glucose or 106 g of bread [124]. Plasma glucose levels were decreased by 28 % and 35 %, compared to glucose and bread without polydextrose, respectively, with significantly reduced serum insulin levels in the glucose plus polydextrose group [124]. These observations indicate that polydextrose could reduce the absorption of glucose. When the effect of polydextrose was studied with human subjects with impaired glucose tolerance or impaired fasting glucose, no change in plasma glucose or insulin has been observed [52]. However, this study [52] had a moderately high fructose intake which could have affected the results as fructose does not induce endogenous secretion of insulin [125]. Diurnally polydextrose did not seem to change plasma sugar levels, but a decrease in insulin after meals was noted [69]. In dogs, polydextrose showed an attenuated postprandial glycemic and lower relative insulin responses than the control sugar maltitol [126].
Polydextrose has been also studied in trials in which the reference group received a normal meal/snack with glucose, and the intervention group the same but with the glucose partially replaced with polydextrose. In volunteers with type 2 diabetes, cranberries with 10g of polydextrose showed attenuated plasma glucose and insulin response compared to cranberries with glucose [127]. In one study with healthy adults, significantly lower postprandial glucose levels were observed after ingestion of strawberry jam with 40 % polydextrose than after ingestion of strawberry jam sweetened with sugar, corn syrup, or apple juice, but this study did not measure insulin [128].
These above results indicate that polydextrose might have a role in postprandial glucose absorption and insulin response. One good candidate to modify insulin response is again the SCFAs, especially propionate, which have been shown to improve insulin sensitivity during glucose tolerance tests [95]. Polydextrose also might interfere the release and absorption of the glucose in the small intestine which would lead to slower and lower blood sugar rise [5]. In some of these studies the response is observed because polydextrose was used as sugar substitute to lower the caloric content of the snack/product [127, 128]. In [127] the beneficial insulin reduction was observed not to be in 1:1 ratio with caloric reduction so there might be additional beneficial effect apart from lowering the overall calorie content.
Meals dense in fiber have also been demonstrated to be able to control the sense of hunger, satiety, inhibit the desire for another meal, or induce satiation, limit the size of the meal, possibly by lowering caloric density or slowing down gastric emptying [40, 129] This would further decrease the sugar load of the individual, since high-fiber diets usually have a lower glycemic load.
Polydextrose has been observed to significantly reduce the feeling of hunger in subjects with impaired glucose metabolism [52], and to have tendency towards reduced snacking [10]. It has been shown to increase satiety and to reduce food intake when combined with yoghurt preloads [130]. However, evidence has been conflicting - in one study when 25 g polydextrose was preloaded in two servings before lunch, no difference in the desire to eat, sense of hunger and fullness was observed beween polydextrose and the other fibers tested [131]. In this study polydextrose did not decrease the energy consumed in lunch. In another study when polydextrose was consumed as 9.5 g in a muffin no difference in the feeling of hungriness or food intake was observed between polydextrose and the other fibers studied [132]. In the two most recent studies, polydextrose intake of 12 g in a fruit smoothie, consumed as a single dose preload, significantly reduced the intake of energy in a buffet lunch 1 hour after the consumption of the smoothie [133]. Similar observations with a single dose of 6.25 g or 12.5 g of polydextrose before a test lunch were also made in another study [134, 135].
Both butyrate and propionate have been shown to induce gut hormones and reduce food intake [136]. Propionate has been shown to act as a satiety-inducing agent, with strong effects on energy intake and feeding behaviour with significantly greater feeling of fullness and lower desire to eat [137, 138]. This could be introduced by the modulation of the colonic mucosa secreted peptide hormones that regulate appetite, such as glucagon like peptide -1 (GLP-1), peptide YY (PYY), oxyntomodulin, or SCFA receptors, GPR43 or GPR41, which have been localized in intestinal enteroendocrine L cells, that are responsible for the production of the appetite regulating hormones [139, 140] but whether polydextrose ingestion causes changes in these peptide hormones remains to be investigated.
Microbial metabolites have been shown to modulate gene expression, for instance butyrate acts as a histone deacetylase (HDAC) inhibitor, and affects gene transciption [141]. Polydextrose has been shown to increase expression of PPARγ in the colon of mice [142]. This has been attributed to be mediated at least by butyrate, which can not only up regulate gene expression of PPARγ, but also activate it [143]. When intestinal epithelial cells were treated with polydextrose fermentation metabolites, a gene expression signature was induced that approached the response of butyrate [144]. In the study [144] 1 or 2 % polydextrose was fermented in a four-stage semicontinuous colon simulation model, in which each vessel in sequence represents different parts of the colon. Caco-2 cells were treated with the polydextrose fermentation metabolites from each vessel, and the idea was to analyse gene expression pattern of the Caco-2 cells treated with fermentation metabolome representing the whole colon. The weakness of this study was that the cells were not differentiated, but were used as a cancer cell model, and that fermentation metabolites originated from a fecal sample only from one individual. In the gene ontology analysis of this study, enrichment of class "lipid metabolism" by the polydextrose fermentation metabolites was noted, which indicated that genes involved in energy metabolism were regulated. Indeed, induction of PPARα, PGC-1α, and Lipin 1which are major regulators of the metabolism, were observed. Additionally, some PPARα responsive genes were observed to be up regulated, such as SORBS1, LPIN1, NPC1, FATP1, HMOX1, and ACSL1 [144].
In the intestine, activation of PPARα results in the specific induction of genes involved in fatty acid uptake, binding, transport, and catabolism. In addition, genes involved in triacylglycerol and glycerolipid metabolism have been suggested to function as fatty acid sensors, and in nutrient absorption [145, 146]. PGC-1α participates to the regulation of both carbohydrate and lipid metabolism, and it has been involved in the adaptation of and maintenance of energy homeostais in caloric restriction [147]. Drosophila PGC-1α homolog increases mitochondrial gene expression and activity and protects against age-related loss of intestinal homeostasis and integrity, and is suggested to extend life span [148]. Lipin 1 is induced by PGC-1α in liver and acts to amplify PGC-1α and to activate many of the genes of mitochondrial fatty acid oxidative metabolism [149]. Lipin 1 has been associated with insulin sensitivity in adipose tissue and liver which indicates that it has a profound role in maintaining systemic metabolic homeostasis [150, 151].
One of the genes regulated by polydextrose fermentation metabolites was Niemann Pick C1 (NPC1), a significant contributor to plasma HDL cholesterol formation [152]. NPC1 facilitates the movement of cholesterol to ABCA1, a cholesterol transporter that is located in the basolateral membrane of enterocytes, that is involved in the efflux process of cholesterol to circulating HDL particles [153]. Approximately 30 % of the steady-state HDL was contributed by the intestinal ABCA1 in mice [154]. In NPC1 deficient cells the HDL cholesterol formation is reduced [155].
Based on the current research there is clear evidence that polydextrose has the ability to attenuate glucose absorption, reduce insulin response and lower blood LDL, total cholesterol and triglyceride levels. HDL cholesterol shows a tendency to be increased, but this has not been consistently demonstrated in all studies. This kind of ability to increase HDL would be quite unique among soluble fermentable fibers. Animal studies also indicate that polydextrose could interfere with cholesterol and triglyceride absorption.
Figure 3 summarises the possible mechanisms of how polydextrose could affect cholesterol and lipid metabolism. Polydextrose is used as a bulking agent, and increases the bulk of the material that transits along the colon. This can provide a sense of fullness and satiety. The effect of polydextrose on bile acid secretion cannot be definitely concluded at this point but is unlikely due to its non-viscous characteristic. It seems, that polydextrose attenuates the blood glucose raising potential of glucose itself, and the insulin response. Glucose and insulin are linked to hepatic de novo cholesterol synthesis, cholesterol absorption and HDL formation. The mechanism of the lipid metabolism modulating effect of polydextrose might be indirect, through its fermentation by the indigenous microbiota either the luminal or mucosal, that at the same time increase SCFA production. The microbiota can affect cholesterol degradation, but could also for instance affect chylomicron formation and cholesterol absorption. The absorbed SCFAs, propionate and butyrate, are linked to diminishing de novo cholesterol synthesis in the liver. Acetate, in contrast, has an opposite effect. Whether SCFAs are the molecules exerting the effect of the polydextrose is not known. During the fermentation of soluble fibers other metabolites apart from SCFAs are formed [156]. The complex structure of polydextrose facilitates its fermentation throughout colon. This differentiates it from other fibers which are fermented early in the colon, and it serves as an energy source for bacteria throughout the colon, and changes in the composition of the microbiota are observed with an increase in butyrate-producing bacteria [114]. It is possible that due to its fermentation characteristics the long-term effect on microbiota composition might be different to other soluble fibers. The mechanism of polydextrose might also be direct, through modulation of surface receptors, but currently there is no evidence for this.
The microarray study has given ideas of how polydextrose fermentation metabolites might affect the intestinal tissue. The evidence is, however, at the transcriptional level only, and is speculative. Additional studies in the possible regulation of PPARα, PGC1α, Lipin1, NPC1, and others by polydextrose is thus needed. In vitro studies could be used for instance to study the role of polydextrose fermentation in HDL formation using a differentiated Caco-2 cell model which has shown to be good model to study de novo ApoA-I production [157].
Summary of the polydextrose function in lipid metabolism.
It could be worthwhile to investigate to what extent polydextrose fermentation metabolites cause systemic effects for instance in liver, and its de novo cholesterol synthesis, not forgetting the role of the intestine. When lipidemic conditions are normal, the liver is the most important site of cholesterol biosynthesis, followed by the intestine. Biosynthesis in the liver and intestine account for about 15 and 10 %, respectively, in the total amount of cholesterol biosynthesis each day [158] [159]. In hypercholesterolemia, when cholesterol biosynthesis is supressed in most organs by fasting, the intestine becomes the major site of cholesterol biosynthesis, and its contribution can increase up to 50 %[160, 161]. Mixtures of short chain fatty acids have been show to suppress cholesterol synthesis in the rat liver and intestine [162], and whether fermentation metabolites from polydextrose can inhibit cholesterol biosynthesis in the intestine, or even in the liver, is an open question.
Michael Bond, Stuart Craig, and Kirsti Tiihonen (DuPont Nutrition and Health) are thanked for their valuable contribution on the manuscript.
The incidence of liver cancer is growing worldwide [1, 2] and research estimates that millions of people will be affected by the disease annually by 2025 [3]. Hepatocellular carcinoma (HCC) describes the most common type of liver cancer, responsible for nearly 90% of all cases. The most significant risk factor for HCC development is infection with the hepatitis B virus (HBV), accounting for 50% of all cases [4]. With antiviral drugs, patients have achieved sustained virological response (SVR), reducing the risk of hepatitis C virus (HCV) infection substantially [5]. Nevertheless, the risk of HCC for individuals with cirrhosis remains even after HCV clearance. Nonalcoholic steatohepatitis (NASH) is becoming the main cause of HCC in the West, since it is associated with metabolic syndrome and diabetes mellitus [6]. Furthermore, there have also been reports that aristolochic acid and tobacco are potentially pathogenic cofactors for HCC [7].
The incidence of HCC differs depending on the etiology and type of genotoxins, although there is a greater understanding of the pathophysiology and drivers of HCC over the past few years; clinical applications of these insights have yet to emerge. There are actionable mutations of HCC tumors in approximately 25% of cases; however, most mutations are less than 10%, making proof-of-concept studies difficult [7, 8]. The majority of mutations in HCC remain unsolvable, including those in TERT, TP53, and CTNNB1 [9]. Researchers are also still working on how to establish biomarkers that guide therapy based on molecular and immune classes.
Since the early 2010s, HCC management has vastly improved [8, 10, 11, 12]. The mainstay curative treatments in HCC cases have been hepatic resection and liver transplantation. For tumors down-staged beyond Milan criteria, refinements in patient selection have led to improved surgical resection results and outstanding 10-year post-liver transplantation survival rates [10, 13]. In nonsurgical early-stage HCCs, image-guided ablation using radiofrequency remains the gold standard despite advancements in alternative approaches [12]. Following these potentially curative methods, adjuvant therapies to prevent relapse are an unmet medical need, as randomized controlled trials (RCTs) have so far given poor results. The most frequently used and standard treatment for intermediate-stage HCC for the past two decades has been transarterial chemoembolization (TACE) [14]. Transarterial radioembolization (TARE) has been demonstrated to be effective in phase II studies [15], but guidelines have not yet established it as a primary standard of therapy. The arsenal of intermediate therapy is unlikely to improve in the immediate term with more locoregional devices or radiation oncology methods.
There has been a threat to the use of traditional HCC treatments from systemic medicines, such as tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and monoclonal antibodies. Patients with HCC are predicted to be exposed to systemic therapy 50–60% of the time over their lives, especially in advanced stages of the disease [8]. The development of systemic medicines has progressed dramatically in the last 5 years, with studies showing significant improvements in overall survival and quality of life for patients [8]. As a result of the combination of anti-PDL1 antibody atezolizumab and anti-VEGF antibody bevacizumab, patients with advanced-stage HCC have a quadrupled life expectancy and improved patient-reported outcomes [16]. The most successful single-drug therapies are still sorafenib [17] and lenvatinib [18]. Regorafenib [19], cabozantinib [20], and ramucirumab [21] have similarly shown enhanced survival advantages when switched to single-agent regimens. In 15–20% of responders, single-agent ICIs produce significant therapeutic advantages, although biomarkers have thus far failed to identify this group [22, 23]. Phase III trials are also underway that examine combinations of ICIs with TKIs or PD1/PDL1 axis inhibitors with CTLA4 inhibitors to examine the efficacy of these therapies. The findings of these studies are expected to alter the landscape of managing HCC at all stages of the disease.
In 2018, there were 841,080 new cases of liver cancer, making it the sixth most common cancer worldwide and the fourth leading cause of cancer-related death [3]. Despite an increase in HCC incidence and mortality in different parts of Europe and the United States [24], the highest rates are seen in East Asia and Africa. SEER reports that HCC has been the fastest-growing cancer-related cause of death in the United States since the early 2000s. HCC is expected to be the third leading cause of cancer-related death by 2030 if current trends continue [25].
Chronic liver disease is responsible for more than 90% of all cases of HCC. All forms of cirrhosis are major risk factors for HCC [10, 11]. Annually, 1–6% of patients with cirrhosis die of HCC. HBV and HCV infection, chronic alcohol consumption, and diabetes- or obesity-related NASH all increase the risk for HCC [26]. Hemochromatosis, antitrypsin deficiency, and cirrhosis from primary biliary cholangitis all represent less common risk factors for HCC. Up to 45% of people with hemochromatosis who develop cirrhosis over their lifetime will develop HCC [27].
The cause of HCC in Asia and Africa is 60% HBV infection, while it is 20% in the West [4]. HBV is a DNA virus that can cause insertional mutagenesis and activate oncogenes by integrating into the host genome [28]. HBV increases the risk of liver cancer even if there is no cirrhosis in most patients with HBV-induced HCC. Due to the high prevalence of endemic HBV in East Asia, males (40 years of age) and females (50 years of age) have a high risk of developing HCC, which necessitates surveillance programs. The incidence of HCC in patients in their early 30s or 40s in Africa is likely due to their exposure to aflatoxin B1, a carcinogen, which increases the risk of developing HCC in combination with HBV [29]. Many Asian countries still do not have universal immunization programs, despite the fact that HBV vaccination programs have reduced HCC incidence in some regions [30].
The most common underlying liver disease in North America, Europe, and Japan is chronic HCV infection [4]. In contrast to HBV, HCV is an RNA virus that does not integrate into the host genome, so those who develop cirrhosis or chronic liver disease with bridging fibrosis are at risk of developing HCC. Direct-acting antiviral (DAA) medications have enabled more and more people to achieve a sustained viral response (SVR), thereby reducing their risk of developing HCC by 50–80% [5]. A number of patients, especially those from minority racial or ethnic groups and those from low-income socioeconomic areas, have not been tested for HCV and thus have no idea of their infection [31]. Additionally, people with HCV-induced cirrhosis remain at risk of developing HCC even after they have achieved sustained virologic response (>2% per year) and, thus, they have to be monitored closely [32, 33].
HBV surface antigens are necessary for HDV to replicate and infect. HDV is an RNA virus. Twenty to forty million people are estimated to be infected with HDV worldwide, and these individuals experience more severe liver disease, notably fibrosis and cirrhosis, than people who have only HBV. Furthermore, several cohort studies have found that co-infection with HDV and HBV may lead to an increased risk of HCC than HBV infection alone. A study reported that patients with acute or chronic HDV infection were at a significantly higher risk of HCC than those with a sole HBV infection [34].
A fatty liver, cirrhosis, and HCC are all caused by excessive alcohol consumption. Cirrhosis caused by persistent alcohol consumption, also known as NASH, is becoming increasingly common. HCC is associated with alcohol-induced cirrhosis in 15–30% of cases depending on geographic region, with an annual incidence varying between 1% observed in population-based studies and 2–3% recorded in tertiary care referral centers [35]. There is also evidence that chronic alcohol consumption increases the risk of HCC from other causes; for example, several studies suggest that those who drink alcohol and are HBV carriers are more likely to develop HCC [36]. Although alcohol consumption has some similarities with other forms of cirrhosis, particularly NASH, in some pathophysiological processes, there is an indication that alcohol consumption may have different pro-tumorigenic mechanisms in individuals.
Patients with diabetes mellitus or obesity may also develop HCC from NASH, another major factor contributing to cirrhosis. Due to the rising incidence of obesity, NASH has become a leading cause of cirrhosis around the world. Since 2010, the proportion of HCC caused by NASH has risen quickly, now accounting for 15–20% of cases in the Western world [6]. The proportion of metabolic syndrome and NASH attributable to the population is expected to exceed 20% due to the co-occurrence of these two disorders [37]. The incidence of HCC in NASH-associated cirrhosis (1–2% per year) is lower than in virus-related cirrhosis (3–5% per year), but it remains >1.1% per year, demonstrating that surveillance is cost-effective [38]. Several studies have shown that 25–30% of NASH-related HCC occurrences develop without cirrhosis, limiting the relevance of current surveillance programs that primarily target individuals with cirrhosis. However, the National Veterans Affairs Health System has discovered that the incidence of HCC annually is below the cost-effective threshold in people with non-cirrhotic NASH and surveillance should not be performed [38, 39].
Many sociodemographic factors have been linked to HCC, particularly in individuals with cirrhosis. The risk of HCC increases with age, with those over 70 years of age showing the highest incidence [40]. HCC is also disproportionately male (male-to-female ratio of 2–3:1), which may reflect a clustering of risk factors among men, as well as differences in sex hormones [41]. HCC is more common in racial or ethnic minorities, particularly Hispanics, than in White people, according to studies. This disparity in prevalence could be related in part to the increased prevalence of single-nucleotide polymorphisms in PNPLA3, which are connected to NASH-associated HCC [42]. Smoking has also been linked to an increased risk of HCC in epidemiological studies [43]. Except for studies demonstrating a protective benefit of coffee and aspirin [44], the impact of diet in reducing the incidence of HCC is unknown.
HCC pathophysiology is a multistep process. The early stages of hepatocyte malignant transformation and HCC development are caused by the interaction of several variables. The cellular environment, immune cells, and the severity of chronic liver disease must all be considered, including genetic predisposition, and reciprocal interactions among viral and nonviral risk factors. From the early stages of transformation to invasion and then metastasis, the microenvironment plays an important role in cancer progression.
HCC’s cell of origin is a point of contention. It is possible for liver cancer to originate from liver stem cells, transit-amplifying populations, or mature hepatocytes, just like in any other type of cancer. There is general controversy over whether liver stem cells exist and function. Additionally, mature hepatocytes have a high proliferation capacity after injury, which allows them to survive for long periods of time. Several studies on mouse models reported that HCC is believed to develop from transformed mature hepatocytes; however, other studies suggest HCC may originate from putative stem cells in the liver [45]. Intrahepatic cholangiocarcinomas and tumors with mixed HCC or cholangiocarcinoma form, on the other hand, often appear to emerge from adult hepatocytes, highlighting the principles of metaplasia and cell plasticity (i.e. trans-differentiation). These data back the idea that a tumor’s form and epigenetic landscape may not always represent its cell of origin [46, 47].
High-throughput next-generation sequencing has identified cancer-driver genes recurrently changed in HCC with oncogenic or tumor-suppressive properties. In 80% of cases of HCC, driver gene alterations are found in the TERT promoter, chromosome translocations, telomerase activation, and gene amplification [7, 48]. Studies have shown that mutations in AXIN1 (inhibitors of the Wnt pathway), CTNNB1 (encoding-catenin), or APC (inhibitors of the Wnt pathway) inactivation activate the Wnt-β catenin signaling pathway in 30–50% of cases [7, 48]. CCNE1, TP53, ARID1A, RB1, CCNA2, PTEN, RPS6KA3, ARID2, and NFE2L2 are all known to have mutations or genetic changes that affect cell cycle control. AKT-mTOR and MAPK pathways, as well as genes involved in epigenetic regulation and oxidative stress, have been linked to HCC. AKT-mTOR and MAPK pathways, as well as genes involved in epigenetic regulation and oxidative stress, have been linked to HCC. The recurrent overexpression and activation of oncogenic signaling pathways, including receptor tyrosine kinases, are also linked to focal chromosomal amplification of MYC, CCND1, VEGFA, FGF19, and MET [49]. In spite of the fact that cancer-driver gene mutations can occur at random, certain genes seem to be associated with specific molecular HCC subclasses based on transcriptome profiles and histological phenotypes [8, 9, 50]. At least 20–25% of HCC patients have a potentially actionable mutation, according to current standards [7, 8, 51]. In the pathogenesis of HCC, it has been well documented that risk factors cooperate with cancer-driver mutations. In patients with a GSTT1 null mutation, for instance, the harmful effects of aflatoxin B1 are amplified by HBV infection [52, 53]. In addition, patients who use a lot of alcohol are more likely to have polymorphisms in PNPLA3, TM6SF2, and HSD17B13 [54, 55].
The TERT promoter is the most common locus of HBV-mediated insertional mutagenesis, resulting in overexpression of telomerase, the enzyme responsible for telomere length maintenance [56]. Telomerase activation inhibits the chromosomal erosion that occurs naturally with each cell division as people age. Telomerase activity on the ectopic enhances cell transformation and protects cells against senescence [57]. Other HBV-associated recurrent insertions have been shown to activate potent oncogenes involved in cell cycle control, such as CCNA2 or CCNE1. Replicative stress and complex rearrangements are caused by these oncogenic changes throughout the genome [58]. Adeno-associated virus 2 (AAV2) showed identical insertional oncogenic mutagenesis in a small group of HCC patients, with a shared hot point of the viral insertion inside the TERT promoter, CCNA2, and CCNE1 [59]. These findings show that viral infection activates particular oncogenes, which act as early facilitators of hepatocyte transformation. HCV infection, on the other hand, has no direct carcinogenic effect, and the induction of mutations is driven by the oxidative stress caused by persistent inflammation.
Hepatocytes are subjected to multiple genetic mutations and epigenetic alterations throughout the progression of chronic liver disease and cirrhosis, which are the most common causes of HCC. Several risk factors that cause DNA changes are linked to particular mutational signatures during this process [7, 60]. In exome sequencing analyses of HCC, patients from Asia and Africa who had been exposed to aristolochic acid (A > T mutations in CTG trinucleotide) and aflatoxin B1 (C > A mutations) had mutational signatures 22 and 24, respectively [7, 61]. Mutations of the C > A at dinucleotide sequences in signature 4 were linked with tobacco smoking, while the T > C mutations at TpA dinucleotide in signature 16 were related to alcohol consumption [62]. It remains to be seen whether this discovery can be turned into preventative measures. It is well known that the liver is capable of detoxifying a variety of chemicals that may cause mutations in the hepatocyte genome, leading to the development of cancer.
Several studies have created a molecular and immune categorization for HCC based on genomic, epigenomic, histopathological, and immunological analysis [1, 9, 63]. Molecular classes of HCC have been identified based on the principal molecular drivers and pathways involved [9, 63, 64, 65, 66, 67] or the tumor’s immunology status [8, 68]. The molecular classifications are associated with specific genomic abnormalities, histological signatures, and clinical outcomes. Approximately half of all HCCs are of the proliferation type [49]. The proliferation type is characterized by mutations in TP53 and FGF19 or CCND1 amplification, and it is more common in HBV-associated cancers with poor prognosis. Within the proliferation class, there are two subclasses: proliferation progenitor cells and proliferation-Wnt-TGF cells. Twenty-five to thirty percent of HCC are proliferation-progenitor cells, which are characterized by activation of classical cell proliferation pathways, i.e. the expression of progenitor cell markers (such as EPCAM and FTP) is also related to the activation of signaling pathways (PI3K-AKT-mTOR, RAS-MAPK, and MET and IGF signaling cascades [49, 64]. In alcohol- and HCV-related HCC, non-proliferative tumors represent more than half of all cases; these tumors have better outcomes and correspond to TCGA cluster 2 [65]. Within the nonproliferative class, at least two distinct subgroups have been described: one with dominant canonical Wnt signaling and mutations in CTNNB1 [69] and the other with IFN signaling activation [49].
Reports on the classification of HCC based on immune cell status have added to the knowledge of HCC’s molecular characteristics [68]. This categorization classifies HCC tumors into four subclasses: immunological-active, immune-exhausted, immune-intermediate, and immune-excluded, and gives additional information based on immune features. Immune cell infiltrations are categorized into two subclasses: immune-active and immune-exhausted. In HCC tumors that are immune-active, helper T (CD4+) and cytotoxic T (CD8+) cells are enriched and ICIs are effective. The depletion of CD8+ cells driven by TGF is prevalent in immune-exhausted tumors. In contrast, immune-excluded tumors lack T cell infiltrates and are characterized by a disproportionate increase in regulatory T cells (Tregs), as well as canonical Wnt signaling and other immune-suppressive pathways. Immune-excluded tumors often develop ICI resistance [70].
Obesity has been related to a higher risk of cancer in a variety of organs [71]. Obesity can cause systemic alterations, such as impaired immune function and endocrine abnormalities, which are common in cancers of many types. According to current research, fatty liver disease is quickly becoming the primary cause of HCC in the Western world [6]. The effects of metabolic and oxidative stress, immune dysfunction, abnormal inflammatory responses, impaired endocrine, and adipokine signaling have all been identified as pathways by which NAFLD or NASH cause HCC (Figure 1) [72, 73].
The molecular mechanism of HBV-induced HCC.
Several classical cell proliferation pathways are activated in HBV-associated HCC tumors, including PI3K-AKT-mTOR, RAS-MAPK, MET, and Wnt-TGF. A high chromosomal instability level and frequent TP53 and AXIN1 mutations are additional features of HBV-induced HCC (Figure 2).
The molecular pathogenesis of HCC induced by NASH, HCV, HDV, and alcohol.
Nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and hepatitis C virus (HCV) infection promote the development of HCC tumors. Here, the risk factors cause chromosomal instability with frequent mutations in the TERT promoter sequence which, in turn, leads to the CTNNB1 mutations and activation of either WNT-β-catenin signaling pathway or IL6-JAK-STAT signaling pathway. The activation of either or both of these signaling pathway promote the proliferation of progenitor cells leading to an inflammatory tumor microenvironment and ultimately to HCC.
Fatty acid overload causes oxidative stress and endoplasmic reticulum (ER) stress in hepatocytes, resulting in pathological inflammation and cell death [72, 74]. HCC was induced in one study in mice following ER stress-induced inflammation via NF-κB and TNF-α signaling pathways [75]. These toxicological processes of HCC, however, are yet to be demonstrated in human. Hepatocytes with abnormal fatty acid metabolism are susceptible to DNA damage caused by reactive oxygen species (ROS) resulting from mitochondrial dysfunction [76]. Hepatocytes are also affected by changes in the expression of particular metabolic enzymes, which reduces their ability to repair DNA damage [77]. Changes in inflammatory signaling are also a result of the metabolic failure; for example, elevated levels of IL-17 (a tumor-promoting cytokine) have been seen in human NASH [78]. A number of pathogenic lipids are produced as oncometabolites in NASH in addition to increased lipid production [79, 80]. When mTORC2 is continuously activated in mouse hepatocytes, a high level of glucosylceramide is produced, increasing ROS production, which can lead to HCC [79]. Alterations in cholesterol metabolism may also have a role in HCC pathogenesis [80], possibly by causing the generation of pro-tumorigenic nuclear receptor ligands. Although autophagy has antitumor properties, one study found that lipophagy (autophagic destruction of lipid droplets) plays a crucial role in HCC progression. Hepatocytes from NASH patients and a mouse model of HCC overexpress sequestosome 1 (also called p62), a lipophagy regulator [81]. Patients with NASH had a higher risk of HCC than those with NAFLD according to studies [6]. In one experiment, fatty acid-induced oxidative stress in hepatocytes increased the expression of STAT1 and STAT3, two pro-inflammatory transcription factors that generally operate in tandem [82]. Surprisingly, a high level of STAT1 promoted NASH progression in this mouse model, while a high level of STAT3 promoted HCC, both independently [82]. Accordingly, similar inflammatory signals may promote progression from NAFLD to NASH or HCC in different ways. This is because NAFLD is more common in the general population than NASH [6]; the data indicate the need to understand how NAFLD, regardless of NASH, can lead to HCC. When hepatocytes are overloaded with fatty acids, the increased ER stress, pathological lipophagy, ROS generation, and a lowered reducing power (low NADH or NADPH levels) may combine to generate oncogenic genetic changes and accelerate the development of malignant cells.
Based on transcriptomic-based phenotypic classes, hepatocellular carcinoma (HCC) can be divided into two primary molecular groupings [49, 64, 65, 66, 67]. More aggressive tumors with weak histological differentiation, high vascular invasion, and higher levels of alpha-fetoprotein (AFP) belong to the proliferation class [50]. In S1 or iCluster 3 [64, 65], Wnt-TGF activation leads to an immune-exhausted phenotype [68], while in S2 or iCluster 1 [64, 65], stem cells markers (CK19, EPCAM) as well as IGF2 and EPCAM signaling pathways are expressed [50]. In hepatitis B virus (HBV)-associated tumors, cell proliferation pathways such as PI3K-AKT-mTOR, RAS-MAPK, MET, and IGF are usually activated. Furthermore, numerous TP53 mutations, high chromosomal instability, and widespread DNA hypomethylation are also characteristics of this group. The nonproliferation class consists of tumors that are less aggressive, well-differentiated histologically, have low AFP levels, and have fewer vascular invasions [50]. These tumors can be caused by nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or infection with hepatitis C virus (HCV) [49, 64, 65, 66, 67]. This class is divided into two distinct subgroups: the WNT––catenin CTNNB1 subclass has frequent CTNNB1 mutations and activated WNT––catenin signaling, leading to an immune-excluded phenotype with low immune infiltration [49, 67, 68]; and the interferon subclass has a highly activated IL6-JAK-STAT signaling pathway, leading to a more inflamed microtumor with many TERT promoter mutations, and this class has chromosomal stability [63, 64, 65, 66, 67, 68].
The histological characteristic of NASH is immune cell infiltration of the obese liver [72]. The establishment of animal models that accurately reproduce human HCC is critical for basic pathogenesis research as well as translational research [83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97]. Immune cells and cytokines have been found to have an essential role in the pathogenesis of HCC in several experimental types. In mouse models, for example, persistent NASH causes CD8+ T cell activation, which leads to hepatocyte destruction and HCC [98]. As a consequence of NAFLD, intrahepatic CD4+ T cells are selectively depleted, which are necessary to initiate an effective adaptive immune response against tumors [99]. Additionally, B cells, Treg cells, natural killer cells, and other myeloid cells have been associated with NASH-induced HCC [72, 73]. The activation and recruitment of platelets in the liver also contribute to HCC formation in mice, specifically via platelet glycoprotein Ib (GPIb) signaling, which is in line with clinical data [100], implying that this pathway has the therapeutic potential [101]. The causal function of NASH in HCC was also linked to a changed cytokine milieu [74]. NASH, for example, has been demonstrated to overexpress hepatic IL-6 and TNF-α, which are both causes of HCC in various etiologies [102].
On the background of fatty liver disease, all of the mechanisms described earlier could promote HCC at the same time. Their relative involvement to human HCC, however, is uncertain at this time. The comparison of mutational signatures in NASH-associated HCC versus HCC from other causes should aid in determining the relative contributions of different variables.
HCC is an archetypal inflammation-related malignancy, with chronic inflammation caused by viral hepatitis, excessive alcohol consumption, NAFLD, or NASH accounting for 90% of the HCC burden. In the development of HCC [103], the immunological microenvironment plays a critical role. Immune infiltrates are associated with a better prognosis in HCC, possibly due to more effective antitumor immunity [68, 104]. Immune signals such as IL-6, lymphotoxin-, and TNF-α have been shown to accelerate hepatocarcinogenesis and impact tumor aggressiveness in mouse models of HCC [47, 105], yet immune responses can also slow the course of liver cancer [103]. In addition, the liver has the greatest number of immune cells in the body and has a unique immunological state that allows it to survive the constant influx of inflammatory signals coming from the gut [103]. Understanding this specific hepatic immune system is likely important given the intricate interplay between malignant hepatocytes and the liver immune system [103, 106]. A surprising finding in mice and humans is that VEGF released by malignant hepatocytes creates an immune-tolerant, pro-tumorigenic microenvironment [49, 107], suggesting that inhibiting the VEGF cascade might have a positive effect on liver immunity by modifying VEGF production. Interestingly, the combination of ICIs and certain targeted medicines such as VEGF inhibitors had greater survival advantages than the use of single agents [16, 108].
It has been shown that hepatocytes in chronically inflamed livers interact with numerous cell types including macrophages, endothelial cells, stellate cells, and various types of lymphocytes [103, 106]. Due to its importance in immuno-oncology therapy, researchers are paying more attention to the adaptive immune system’s involvement. Mouse models have revealed that practically every immune cell type can play both pro-tumor and antitumor roles [103]. In addition to producing pro-tumorigenic cytokines and growth factors that support tumor cell proliferation or inhibit apoptosis, immune cells also diminish nearby lymphocytes’ antitumorigenic function. The NF-B and JAK-STAT pathways have been identified as major inflammatory signaling pathways implicated in the promotion of HCC in studies [109], and this assertion was confirmed in a transcriptomic analysis of human HCC [110]. Immune monitoring and the destruction of premalignant or completely changed malignant hepatocytes are the adaptive immune system’s main antitumor functions [104].
The main effectors of antitumor immunity are cytotoxic T (CD8+) cells. As a result, one study found that depleting these T cells in mice increased HCC burden [111], while another found that these T cells promote premalignant hepatocyte surveillance [112]. Several studies in mice have shown that the depletion of CD8+ T cells can also reduce tumor burden [98]. Analyses of human HCC samples suggest that some individuals have functional CD8+ T lymphocytes that produce antitumor effector molecules such as granzyme A, granzyme B, and perforin [113]. However, single-cell sequencing of human HCC T cells has revealed that the CD8+ T cells are often dysfunctional in HCC [114]. There is no clear understanding of the causes of CD8+ T cell dysfunction, which leads to diminished proliferation and the inability to generate cytotoxic effector molecules. Increasing numbers of Treg cells within the tumor are linked with poorer clinical outcomes in HCC, and Treg cells are thought to be a primary cause of T cell dysfunction [115]. Treg cells’ immunosuppressive capabilities may be mediated by CD10 and TGF116 production, suggesting that blocking these cytokines could make HCC more susceptible to ICIs. HCC-infiltrating Treg cells are known to suppress immune responses through the hyaluronic acid receptor, layilin, which is interesting [116]. As a result of a layilin induction, CD8+ T cells exhibited dysfunction in human HCC, and layilin overexpression was associated with distinct mRNA expression signatures in lymphocytes [114].
Although B cells were once assumed to be innocent bystanders in cancer, new data suggest that they have an active role in the adaptive immune system’s interaction with cancer [117]. B lymphocytes both stimulated and inhibited tumor growth in mice models of HCC [118]. Furthermore, one study found that IgA-expressing cells actively suppressed CD8+ T cell activity, which aided HCC growth [111]. Furthermore, studies in humans and mice have shown that tertiary lymphoid structures, which are crucial for adaptive immune responses to cancer [119], have both pro-tumor and antitumor capacity in HCC [120, 121].
The risk of HCC is high enough to warrant surveillance once the patient has reached cirrhosis, even though some etiologies (for instance, HCV versus autoimmune hepatitis) are more likely to cause HCC than others [10, 11]. In response to chronic injury, hepatic stellate cells play an important role [122]. Upon activation, it undergoes phenotypic changes and synthesizes components of the extracellular matrix, mainly collagen, as well as growth factors, which promote neoangiogenesis, endothelial cell migration, and fibrosis [123]. Cirrhosis and portal hypertension have a histological substrate in which the hepatic architecture is distorted and the vasculature is disordered. Premalignant senescent hepatocytes respond to this condition by secreting chemokines that impair senescent surveillance and immune-mediated tumor suppression in vivo [112]. Experimental models have also demonstrated that CD4+ cells are relevant in promoting NAFLD-related HCC [99], and the interaction between the innate immune system and the intestinal microbiota plays a role in promoting the development of HCC [124, 125]. In HCC, the immune system, in addition to fibrosis, plays a significant role in the cancer field effect. The cancer field effect refers to the favorable microenvironment in cirrhosis that favors tumor formation. The primary molecular elements unregulated in this microenvironment have been identified through various genomic investigations. Several gene profiles obtained from cirrhotic tissue are associated with the probability of developing HCC and can be utilized to risk stratify patients [110, 126, 127]. The presence of these gene signatures is associated with cancer risk, the incidence of hepatic decompensation in patients, and overall survival [126, 127]. More research has been done on the genetic characteristics of the cirrhosis inflammatory milieu that contribute to HCC development [128]. In 50% of neighboring cirrhotic tissue from HCC patients, an immune-mediated cancer field molecular subclass was observed. In addition to lymphocyte infiltration, this subclass can be further divided based on pro-inflammatory or immunosuppressive signal activation. In the immunosuppressive subclass, which accounted for 10% of patients and had a threefold higher risk of developing HCC, TGF signaling, T-cell exhaustion, and overexpression of immunological checkpoints (such as CTLA4, TIGIT, and LAG3) were shown to be more prevalent [128]. Modulating the tumor microenvironment’s role in HCC’s natural history would be a compelling reason for altering the dynamic crosstalk between hepatocytes and the hepatic immune system [103].
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Singh",profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8018",title:"Extracellular Matrix",subtitle:"Developments and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/8018.jpg",slug:"extracellular-matrix-developments-and-therapeutics",publishedDate:"October 27th 2021",editedByType:"Edited by",bookSignature:"Rama Sashank Madhurapantula, Joseph Orgel P.R.O. and Zvi Loewy",hash:"c85e82851e80b40282ff9be99ddf2046",volumeInSeries:23,fullTitle:"Extracellular Matrix - Developments and Therapeutics",editors:[{id:"212416",title:"Dr.",name:"Rama Sashank",middleName:null,surname:"Madhurapantula",slug:"rama-sashank-madhurapantula",fullName:"Rama Sashank Madhurapantula",profilePictureURL:"https://mts.intechopen.com/storage/users/212416/images/system/212416.jpg",institutionString:"Illinois Institute of Technology",institution:{name:"Illinois Institute of Technology",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9759",title:"Vitamin E in Health and Disease",subtitle:"Interactions, Diseases and Health Aspects",coverURL:"https://cdn.intechopen.com/books/images_new/9759.jpg",slug:"vitamin-e-in-health-and-disease-interactions-diseases-and-health-aspects",publishedDate:"October 6th 2021",editedByType:"Edited by",bookSignature:"Pınar Erkekoglu and Júlia Scherer Santos",hash:"6c3ddcc13626110de289b57f2516ac8f",volumeInSeries:22,fullTitle:"Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoğlu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoğlu",profilePictureURL:"https://mts.intechopen.com/storage/users/109978/images/system/109978.jpg",institutionString:"Hacettepe University",institution:{name:"Hacettepe University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Proteomics",value:18,count:4},{group:"subseries",caption:"Metabolism",value:17,count:6},{group:"subseries",caption:"Cell and Molecular Biology",value:14,count:9},{group:"subseries",caption:"Chemical Biology",value:15,count:13}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:8},{group:"publicationYear",caption:"2021",value:2021,count:7},{group:"publicationYear",caption:"2020",value:2020,count:12},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:2}],authors:{paginationCount:250,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. 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Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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