1A). Serum cholesterol levels were higher in obese patients; however, we did not observe changes in serum cholesterol between NAFL and NASH (Table 1; Supporting Fig. 2A). In parallel with alterations in FFAs, BA levels were higher in individuals with high NAS (Fig. 1C). Additionally, we observed

a trend towards higher FGF-19 levels in NASH patients, indicating intestinal FXR activation in these individuals (Fig. 1B). Hepatocyte ballooning degeneration is a well-validated histomorphological indicator for hepatocellular injury in NASH and as well a feature of hepatocyte stress in cholestatic liver disease.16 In individuals with advanced ballooning, we found significantly higher serum BA levels (Fig. 2B), a trend towards higher FGF19 levels (Fig. 2F), more check details apoptosis (Fig. 2C,E), and serum markers of hepatocyte cell death (Fig. 2D). Since we previously have shown a protective role for adiponectin in hepatic steatosis, and several authors identified adiponectin as an important mediator

in NAFLD pathogenesis, we aimed to quantify adiponectin in this cohort.3, 17 As expected, serum adiponectin levels were decreased in NASH compared to NAFL within our cohort of morbidly obese patients who underwent bariatric surgery (Fig. 1B). By comparing NAFL with NASH selleckchem within the superobese cohort, and focusing solely on the differences between these two groups further on, we acknowledged the fact that obesity itself is reversely correlated with adiponectin levels as demonstrated in the Supporting data (Supporting Fig. 1). Furthermore, as previously described by others, we found an inverse correlation of adiponectin and the NAS (Fig. 1D) and ballooning progression (Fig. 2A), again underscoring the protective effect of adiponectin. Most likely, as a counterregulatory mechanism, selleck chemicals llc we observed an increase in messenger RNA (mRNA) expression of the adiponectin receptor ApoR2 in NASH, which was associated with hepatocellular apoptosis (Figs. 3E,F, 5). Interestingly,

in addition to our observation that adiponectin is decreased in NASH and BAs increased with progression of the disease, we found a direct inverse correlation of adiponectin and serum BAs, revealing a potential effect of adiponectin on BA metabolism (Fig. 1E). As expected, in NAFLD patients we observed an up-regulation of mRNA expression of death receptors, apoptosis, and fatty acid transport related genes (Fig. 3A). Transcripts of the BA uptake transporter NTCP, which is under physiological conditions repressed by SHP, are up-regulated in obese individuals. However, we observed a decrease in NTCP expression in superobese NAFLD patients compared to “lean” NAFLD. Within the superobese group NASH patients exhibited a further reduction of NTCP in comparison to NAFL, most likely secondary to increased BA levels with FXR and SHP activation (Fig. 3B).

Patients with grossly enlarged livers develop abdominal wall herniation and may report shortness of breath. Other complications are infection, hemorrhage or rupture of a cyst,

compression of the inferior cava, hepatic veins, or bile ducts, but these occur less frequently.2 ADPKD, autosomal dominant polycystic kidney disease; cAMP, 3′-5′-cyclic adenosine monophosphate; mTOR, mammalian target of rapamycin; PCLD, polycystic liver disease; TAE, transcatheter arterial embolization; VEGF, vascular endothelial growth factor. Both DAPT in vitro ADPKD and PCLD are autosomal dominant disorders. Two gene mutations account for almost all ADPKD cases: PKD1, which encodes polycystin-1, accounts for 85% of cases, whereas PKD2, encoding polycystin-2, is responsible for the remainder. PCLD is caused by PRKCSH or SEC63 mutations, although in only 21% of patients a bonafide mutation can be found.11, 12 The protein products of these genes (hepatocystin and Sec63, respectively) act in concert to achieve proper topology and folding of integral membrane or secreted glycoproteins in the endoplasmic reticulum (ER).13 Liver cysts are thought to arise from malformation of the ductal plate during embryonic liver development.

Normal bile ducts arise from the ductal plate through growth and apoptosis. In PLD, complexes of disconnected intralobular bile ductules, also termed von Meyenburg complexes, are retained. These complexes can grow into cysts in adult life and become disconnected as they grow from von Meyenburg complexes.14-16 Probably, abnormalities Pictilisib mw in biliary cell proliferation and apoptosis and enhanced fluid secretion are key elements in the pathogenesis of PLD. Rucaparib nmr In cystic livers, activation of several signal transduction pathways is altered leading to hyperproliferation and hypersecretion. Indeed, vascular endothelial growth factor (VEGF), estrogens, and insulin-like growth factor-1 are overexpressed in hepatic cystic epithelium, and promote cholangiocyte

proliferation in an autocrine fashion.17, 18 Additionally, markedly higher levels of phospho-ERK, phospho-AKT, phospho-mammalian target of rapamycin (mTOR), and its downstream effector phospho-S6 ribosomal protein (S6rp) are found in hepatic cysts.19 Finally, the second messenger 3′-5′-cyclic adenosine monophosphate (cAMP) regulates cholangiocyte proliferation and fluid secretion.20 There are higher cAMP levels in cholangiocytes of ADPKD rodent models, which is associated with cholangiocyte hyperproliferation and cyst expansion.21, 22 There are no specific laboratory test abnormalities of PLD. As a rule, liver synthesis is maintained during all stages of the disease. Gamma glutamyl transferase (gGT) is elevated in 51% and a high alkaline phosphatase (AP) is seen in 17% of PCLD patients.2 The elevated AP and gGT levels probably reflect activation of cholangiocytes.9, 23-26 Serum transaminases are normal or only mildly elevated.

Vascular invasion was noted in one patient. Using tumor-node-metastasis staging of the Union Internationale Contre Le Cancer (UICC) system (6th edition),16 patients were classified as having stage I (n = 39), II (n = 29), IIIA (n = 0), IIIB (n = 0), IIIC (n = 1), or IV (n = 0) tumors. Detection of TAA-specific T cells was performed by direct ex vivo analysis (IFN-γ ELISPOT assay). Positive T cell responses against each TAA-derived peptide were observed in 0 to 11 (0.0%-17.2%) patients before RFA (Table 2). The same responses against HIV- and CMV-derived peptides were observed in 1 (1.6%) and 43 (62.3%) patients, respectively. After HCC Crizotinib price treatments with RFA, positive T cell responses

against TAA-, HIV- and CMV-derived peptide were observed in 8-24 (11.6%-35.3%), 2 (2.9%), and 39 (58.2%) patients, respectively. The increase of the frequency of TAA-specific T cells after RFA observed in 7 of 11 peptides (SART2899, SART3109, MRP3503, MRP3765, Selleckchem RG7420 AFP357, AFP403, and hTERT461) was statistically significant (Table 2). The magnitude of TAA-specific T cell responses determined by the frequency of T cells and the proportion of the patients who showed a significant increase of TAA-specific T cells are shown in Fig. 1. When the T cell responses against a single peptide with more than or equal to 10 specific spots and

two-fold increase were defined as significant, a significant increase was observed in 4-16 (6.5%-24.6%) patients for each TAA-derived peptide and in 24 (39.3%) patients for total of TAA-derived peptides. On the other hand, the numbers of patients who showed a significant increase against HIV- and CMV-derived peptide were 1 (1.6%) and 8 (11.9%), respectively. The number of patients who showed a significant increase

against at least one TAA-derived peptide after RFA was 43 (62.3%). To determine what kind of T cell is responsive to the peptides, TAA-derived peptide-specific IFN-γ–producing T cells were also analyzed by ELISPOT assay using Coproporphyrinogen III oxidase PBMC-depleted CD4+ or CD8+ cells. The assay showed that IFN-γ–producing T cells against the peptides (SART2899, SART3109, MRP3503, MRP3692, MRP3765, AFP357, AFP403, AFP434, hTERT167, hTERT324, and hTERT461) mainly consisted of CD8+ cells (Supporting Fig. 1). To examine the effect of increase of TAA-specific T cells after RFA for the prognosis of patients, we analyzed the relationship between the number of TAA-specific T cells and HCC recurrence-free survival after RFA. First, we divided the patients into two groups with high (above median) and low (below median) specific spots detected via ELISPOT assay. In the analysis, we found that a high number of TAA-specific T cells after HCC treatment correlated significantly with the length of HCC recurrence-free survival (P = 0.044) (Fig. 2A). The difference between the groups was emphasized when 50 spots were defined as highly specific spots (P = 0.006) (Fig. 2B).

2 The implication is that variance in the regulatory elements of the genome carry a large burden of the risk of complex

diseases. Indeed, several GWAS variants in diabetes,3 colon cancer,4 and cardiovascular disease5 reside in enhancer elements. Moreover, these results imply that large-scale sequencing studies focusing on protein-coding sequences (the “exome”) risk missing crucial parts of the transcribed genome (the “transcriptome”) and consequently the ability to identify true causal variants. An international collaborative effort to determine the functional importance of noncoding DNA was developed which generated selleck chemicals llc an encyclopedia of DNA elements (ENCODE).6 This followed a 4-year pilot study initiated in 2003, which demonstrated significant functionality of noncoding elements in 1% of the human genome,7 and the project was scaled up to annotate the entire genomic sequence. A by-product of these efforts was the development of “next-generation” sequencing technologies—including the first ChIP-plus-sequencing assays (ChIP-seq) for transcription factors and histone modifications,8, 9 as well as pioneering RNA sequencing assays (RNA-seq).10 The findings were published in the above flagship article in September 2012, as well as 30 other simultaneously published

research papers. ENCODE demonstrated, using a variety of methodologies, that 80% of noncoding “junk” DNA contains elements with DOK2 biochemical function. The cornerstone of ENCODE is the recognition of biochemical signatures which characterize certain

types of noncoding functional DNA elements. Navitoclax Examples include promoter regions that are rich in predictable biding sites for DNA binding proteins, which can be experimentally verified by site-specific occupancy assays such as ChIP.11, 12 Promoter regions also have alterations in chromatin structure giving rise to nuclease hypersensitivity of the underlying DNA.13 Further characteristics of functional elements are histone modification suggesting transcription factor occupancy of adjacent DNA, and DNA methylation as an epigenetic modulator of gene expression.11, 14 All of these biochemical signatures were experimentally assayed in the ENCODE project. To identify regions of DNA-protein interaction, the binding locations of 119 different DNA-binding proteins and a number of RNA polymerase components were assayed in 72 cell types using ChIP-seq. Overall, 636,336 binding regions covering 231 megabases (8.1% of the genome) were enriched for regions bound by DNA-binding proteins across all cell types. The ENCODE consortium has made the information associated with each transcription factor in FactorBook (http://www.factorbook.org)—a freely available public resource. The accessibility of chromatin to DNase I hypersensitivity was assessed by mapping 2.

In addition, cells that were deficient for LRP1 proved approximately 50% less efficient than their LRP1-expressing counterparts in the uptake and

degradation of FVIII [33,53,54]. Similar results were obtained by blocking cellular LRP1 with its universal inhibitor receptor-associated protein (RAP). Thus, it became apparent that LRP1 participates in the uptake and transport of FVIII to intracellular degradation pathways. However, a message that could easily be overlooked from these experiments is that the absence of LRP1 resulted in but a partial inhibition of FVIII degradation, strongly indicating that alternative pathways contributing to FVIII catabolism should exist. Nevertheless, a vast amount of data has been produced showing that the contribution of LRP1 to FVIII catabolism is of in vivo relevance. These include experiments using GSK3 inhibitor mice with a

conditional induced deletion of the LRP1 gene, which resulted in increased plasma levels of FVIII in these mice [55]. In addition, the mean residence time of intravenously administered FVIII was prolonged 1.5-fold, from 2.5 to 4 h. A number of epidemiological studies revealed that LRP1 http://www.selleckchem.com/products/Methazolastone.html modulates FVIII plasma levels also in humans [56–59]. So far, two distinct LRP1 polymorphisms (LRP1/D2080N and LRP1/A217V) have been suggested to be associated with up to 20% higher FVIII plasma levels [57,58]. The underlying mechanism of how these polymorphisms affect FVIII levels remains to be elucidated. Despite the

Acetophenone proven physiological relevance of LRP1 in FVIII clearance, a number of issues still remain unclear. For instance, LRP1 is known for its large spectrum of structurally and functionally unrelated ligands, with more than 50 ligands currently being identified [60]. It is unknown however, if and how these other ligands affect LRP1-dependent clearance of FVIII. Another point relates to the fact that LRP is able to assemble into heterologous receptor complexes. Examples hereof include platelet-derived growth factor (PDGF) receptor in smooth muscle cells, N-methyl-d-aspartate (NMDA) receptor in neurons and β2-integrins on leukocytes [61–63]. It cannot be excluded therefore that part of the LRP-mediated effects are indirect, in that LRP1 affects the function of other receptors. Direct evidence for this possibility is currently lacking. However, it has been shown that LRP1 is able to modulate FVIII catabolism in concert with other receptors. For instance, Bovenschen et al. [64] demonstrated that LRP1 regulates FVIII levels in a coordinated fashion with LDL receptor, illustrated by a synergistic increase in plasma levels and survival of FVIII in mice with a combined LRP1/LDL receptor deficiency [64]. Of note, also other members of the LDL receptor family are able to recognize FVIII, such as vLDL receptor and megalin [65–67].

In addition, cells that were deficient for LRP1 proved approximately 50% less efficient than their LRP1-expressing counterparts in the uptake and

degradation of FVIII [33,53,54]. Similar results were obtained by blocking cellular LRP1 with its universal inhibitor receptor-associated protein (RAP). Thus, it became apparent that LRP1 participates in the uptake and transport of FVIII to intracellular degradation pathways. However, a message that could easily be overlooked from these experiments is that the absence of LRP1 resulted in but a partial inhibition of FVIII degradation, strongly indicating that alternative pathways contributing to FVIII catabolism should exist. Nevertheless, a vast amount of data has been produced showing that the contribution of LRP1 to FVIII catabolism is of in vivo relevance. These include experiments using Depsipeptide mw mice with a

conditional induced deletion of the LRP1 gene, which resulted in increased plasma levels of FVIII in these mice [55]. In addition, the mean residence time of intravenously administered FVIII was prolonged 1.5-fold, from 2.5 to 4 h. A number of epidemiological studies revealed that LRP1 this website modulates FVIII plasma levels also in humans [56–59]. So far, two distinct LRP1 polymorphisms (LRP1/D2080N and LRP1/A217V) have been suggested to be associated with up to 20% higher FVIII plasma levels [57,58]. The underlying mechanism of how these polymorphisms affect FVIII levels remains to be elucidated. Despite the

Calpain proven physiological relevance of LRP1 in FVIII clearance, a number of issues still remain unclear. For instance, LRP1 is known for its large spectrum of structurally and functionally unrelated ligands, with more than 50 ligands currently being identified [60]. It is unknown however, if and how these other ligands affect LRP1-dependent clearance of FVIII. Another point relates to the fact that LRP is able to assemble into heterologous receptor complexes. Examples hereof include platelet-derived growth factor (PDGF) receptor in smooth muscle cells, N-methyl-d-aspartate (NMDA) receptor in neurons and β2-integrins on leukocytes [61–63]. It cannot be excluded therefore that part of the LRP-mediated effects are indirect, in that LRP1 affects the function of other receptors. Direct evidence for this possibility is currently lacking. However, it has been shown that LRP1 is able to modulate FVIII catabolism in concert with other receptors. For instance, Bovenschen et al. [64] demonstrated that LRP1 regulates FVIII levels in a coordinated fashion with LDL receptor, illustrated by a synergistic increase in plasma levels and survival of FVIII in mice with a combined LRP1/LDL receptor deficiency [64]. Of note, also other members of the LDL receptor family are able to recognize FVIII, such as vLDL receptor and megalin [65–67].

In addition, cells that were deficient for LRP1 proved approximately 50% less efficient than their LRP1-expressing counterparts in the uptake and

degradation of FVIII [33,53,54]. Similar results were obtained by blocking cellular LRP1 with its universal inhibitor receptor-associated protein (RAP). Thus, it became apparent that LRP1 participates in the uptake and transport of FVIII to intracellular degradation pathways. However, a message that could easily be overlooked from these experiments is that the absence of LRP1 resulted in but a partial inhibition of FVIII degradation, strongly indicating that alternative pathways contributing to FVIII catabolism should exist. Nevertheless, a vast amount of data has been produced showing that the contribution of LRP1 to FVIII catabolism is of in vivo relevance. These include experiments using Crizotinib ic50 mice with a

conditional induced deletion of the LRP1 gene, which resulted in increased plasma levels of FVIII in these mice [55]. In addition, the mean residence time of intravenously administered FVIII was prolonged 1.5-fold, from 2.5 to 4 h. A number of epidemiological studies revealed that LRP1 JAK inhibitor modulates FVIII plasma levels also in humans [56–59]. So far, two distinct LRP1 polymorphisms (LRP1/D2080N and LRP1/A217V) have been suggested to be associated with up to 20% higher FVIII plasma levels [57,58]. The underlying mechanism of how these polymorphisms affect FVIII levels remains to be elucidated. Despite the

this website proven physiological relevance of LRP1 in FVIII clearance, a number of issues still remain unclear. For instance, LRP1 is known for its large spectrum of structurally and functionally unrelated ligands, with more than 50 ligands currently being identified [60]. It is unknown however, if and how these other ligands affect LRP1-dependent clearance of FVIII. Another point relates to the fact that LRP is able to assemble into heterologous receptor complexes. Examples hereof include platelet-derived growth factor (PDGF) receptor in smooth muscle cells, N-methyl-d-aspartate (NMDA) receptor in neurons and β2-integrins on leukocytes [61–63]. It cannot be excluded therefore that part of the LRP-mediated effects are indirect, in that LRP1 affects the function of other receptors. Direct evidence for this possibility is currently lacking. However, it has been shown that LRP1 is able to modulate FVIII catabolism in concert with other receptors. For instance, Bovenschen et al. [64] demonstrated that LRP1 regulates FVIII levels in a coordinated fashion with LDL receptor, illustrated by a synergistic increase in plasma levels and survival of FVIII in mice with a combined LRP1/LDL receptor deficiency [64]. Of note, also other members of the LDL receptor family are able to recognize FVIII, such as vLDL receptor and megalin [65–67].

001). LF index (odds ratio [OR] = 5.3, 95% confidence interval [CI] = 2.2–13.0) and platelet count (OR = 0.78, 95% CI = 0.68–0.89) were independently associated with the presence of advanced fibrosis (F3–4). Further, LF index was independently associated with the presence of minimal fibrosis (F0–1) (OR = 0.25, 95% selleck products CI = 0.11–0.55). The area under the receiver–operator curve (AUROC) of LF index for predicting

advanced fibrosis (0.84) was superior to platelets (0.82), FIB-4 index (0.80) and aspartate aminotransferase/platelet ratio index (APRI) (0.76). AUROC of LF index (0.81) was superior to platelets (0.73), FIB-4 index (0.79) and APRI (0.78) in predicting minimal fibrosis. LF index calculated by RTE is useful for predicting liver fibrosis, and diagnostic accuracy

of LF index Akt inhibitor is superior to serum fibrosis markers. “
“Background and Aim:  To evaluate hepatic hemodynamics in patients with nodular regenerative hyperplasia of the liver (NRH) with portal hypertension (PHT). Methods:  We retrospectively reviewed the charts of 24 patients referred for PHT related to biopsy-proven NRH. Hemodynamic measurements included wedged hepatic vein (WHVP) and inferior vena cava (IVCP), and, in 12 patients, portal vein pressure (PVP). Hepatic vein pressure gradient (HVPG: WHVP–IVCP) and portal vein pressure gradient (PVPG: PVP–IVCP) were calculated. Results:  Nodular regenerative hyperplasia was associated in 24 patients with various diseases (oxaliplatin chemotherapy, treatment with purine antagonists, post liver transplantation, hematologic and rheumatologic conditions and HIV infection). Liver function parameters were either completely normal or slightly impaired. Patients were referred for gastroesophageal varices (n = 18), and/or ascites (n = 11), and/or splenomegaly (n = 20). In patients with varices or ascites, HVPG was lower than 10 mmHg (a cut-off point for the presence of varices and/or ascites) in 15/21, suggesting a

pre-sinusoidal component to their PHT confirmed by a PVP higher than 12 mmHg in 12/12 patients. The mean difference between HVPG and PVPG was 8.7 mmHg in these patients. Ten patients were treated by transjugular intrahepatic portosystemic Selleck Baf-A1 shunt. None of them re-bled, and one presented transient hepatic encephalopathy. Conclusions:  Presinusoidal PHT associated with NRH is probably related to compression of portal venules by the regenerative nodules. In patients with HTP and a HVPG < 10 mmHg, the diagnosis of NRH must be suspected and PVP measured, which is important in the management of these patients. "
“Liver biopsy remains an important tool in clinical practice. It should be performed by trained physicians who are able to do the biopsy and manage any possible complications that may arise after the procedure. Liver biopsy can be performed percutaneously, transvenously, or laparoscopically. The choice between the different options depends on the individual patient and local practice.

1). This allows manufacturing of PEG molecules of various sizes and molecular weights depending on the number of subunits needed. Polyethylene glycol molecules are inert, amphiphilic and soluble in water. They remain uncharged and do not contain any specific moieties that would enhance interaction with biological structures in the body, such as receptors or membranes [4]. Polyethylene glycols are more or less polydispers with a range of molecular weights and only an average molecular weight is usually reported. For pharmaceutical use, PEG molecules are produced under well-controlled Good Manufacturing Practice conditions. Current experience Y-27632 concentration with PEGylated therapeutics demonstrates

that they exhibit superior clinical properties when compared with their unmodified parent molecules. They can show reduced toxicity, better physical and thermal stability, greater protection against proteolytic degradation, higher solubility, longer in vivo circulation half-life, lower clearance and therefore enhanced efficacy [1, 13, 19]. The PEG molecule itself is generally considered non-immunogenic, but the immunogenicity of the PEG molecule coupled to a protein may click here reflect the immunogenicity of the protein [4, 12, 13]. Webster et al. conclude that the risk of a severe immune reaction due to the generation

of anti-PEG antibodies is practically negligible due to the weak immunogenicity of PEG and the low amounts of the polymer-protein conjugate usually given as therapy. Several authors have reported that PEGylated proteins show reduced immunogenicity when compared with their unmodified parent molecule

Teicoplanin [4, 12, 13, 20]. Preclinical studies with BAY 94–9027 molecule similarly showed consistently less neutralizing antidrug antibody development in rats, haemophilia A mice and rabbits and in vitro studies indicated that the PEG moiety decreased presentation of the rFVIII to antigen presenting cells, thereby potentially reducing the immunogenicity of FVIII itself [21]. All PEGylated therapeutic proteins undergo preclinical programmes and clinical trials mandated by regulatory authorities. No PEG-specific risk for human health or any safety concerns were identified, when reviewing toxicology and other PEG safety data from a wide molecular range (2–60 kDa) of PEG molecules [12, 13]. The only reported findings were ‘foamy macrophages’ seen in some toxicology studies at high doses, which did not result in any toxicity [13, 22, 23]. Small PEGs and PEG derivatives find many applications in cosmetics and consumer products due to their low toxicity, good solubility and low viscosity. Polyethylene glycols are used in laxatives, toothpastes, hair shampoos, excipients in oral and intravenous (iv) formulations (e.g. Busulfan®) and in hydrogels for tissue engineering [12, 13, 24]. At least 10 PEGylated protein therapeutics have been approved by regulatory agencies (FDA, EMA), and several others are in development [1, 22-29].

1). This allows manufacturing of PEG molecules of various sizes and molecular weights depending on the number of subunits needed. Polyethylene glycol molecules are inert, amphiphilic and soluble in water. They remain uncharged and do not contain any specific moieties that would enhance interaction with biological structures in the body, such as receptors or membranes [4]. Polyethylene glycols are more or less polydispers with a range of molecular weights and only an average molecular weight is usually reported. For pharmaceutical use, PEG molecules are produced under well-controlled Good Manufacturing Practice conditions. Current experience INCB024360 price with PEGylated therapeutics demonstrates

that they exhibit superior clinical properties when compared with their unmodified parent molecules. They can show reduced toxicity, better physical and thermal stability, greater protection against proteolytic degradation, higher solubility, longer in vivo circulation half-life, lower clearance and therefore enhanced efficacy [1, 13, 19]. The PEG molecule itself is generally considered non-immunogenic, but the immunogenicity of the PEG molecule coupled to a protein may ZVADFMK reflect the immunogenicity of the protein [4, 12, 13]. Webster et al. conclude that the risk of a severe immune reaction due to the generation

of anti-PEG antibodies is practically negligible due to the weak immunogenicity of PEG and the low amounts of the polymer-protein conjugate usually given as therapy. Several authors have reported that PEGylated proteins show reduced immunogenicity when compared with their unmodified parent molecule

Ergoloid [4, 12, 13, 20]. Preclinical studies with BAY 94–9027 molecule similarly showed consistently less neutralizing antidrug antibody development in rats, haemophilia A mice and rabbits and in vitro studies indicated that the PEG moiety decreased presentation of the rFVIII to antigen presenting cells, thereby potentially reducing the immunogenicity of FVIII itself [21]. All PEGylated therapeutic proteins undergo preclinical programmes and clinical trials mandated by regulatory authorities. No PEG-specific risk for human health or any safety concerns were identified, when reviewing toxicology and other PEG safety data from a wide molecular range (2–60 kDa) of PEG molecules [12, 13]. The only reported findings were ‘foamy macrophages’ seen in some toxicology studies at high doses, which did not result in any toxicity [13, 22, 23]. Small PEGs and PEG derivatives find many applications in cosmetics and consumer products due to their low toxicity, good solubility and low viscosity. Polyethylene glycols are used in laxatives, toothpastes, hair shampoos, excipients in oral and intravenous (iv) formulations (e.g. Busulfan®) and in hydrogels for tissue engineering [12, 13, 24]. At least 10 PEGylated protein therapeutics have been approved by regulatory agencies (FDA, EMA), and several others are in development [1, 22-29].