Impact of immunogenicity on efficacy and tolerability of tumour necrosis factor inhibitors: pooled analysis of biosimilar studies in rheumatoid arthritis.

Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).

THE INFLUENCE OF TOTAL OR SUB-TOTAL GASTRECTOMY ON GLUCOSE CONTROL IN DIABETIC AND NON-DIABETIC PATIENTS.

OBJECTIVE: Although bariatric surgery including gastrectomy has recently emerged as a useful treatment for type 2 DM with obesity, it is not clear whether gastrectomy itself can have beneficial effects on glucose metabolism. Therefore, in this study, we investigated changes in blood glucose in patients with and without diabetes who underwent gastrectomy. METHODS: From Jan 2010 to May 2014, 77 patients with diabetes and 77 patients without diabetes who underwent gastrectomy at Chonbuk National University Hospital, South Korea, were included. We compared fasting plasma glucose levels and HbA1c value before and after gastric surgery. RESULTS: After gastrectomy, 59 patients (38.3%) showed reduced fasting plasma glucose levels at the 1 year point, and 80 patients (51.9%) exhibited reduced fasting plasma glucose at 3 years, irrespective of their diabetes status. Among 77 patients with diabetes, decreased fasting plasma glucose was observed in 22 (28.6%) and 46 patients (59.7%) 1 and 3 years after gastrectomy, respectively. In patients who exhibited reduced fasting plasma glucose after gastrectomy, the degree of reduced glucose was as follows: 56.4±48.5 vs 23.2±16.1 mg/dL after 1 year, 58.3±52.3 vs 18.4±13.7 mg/dL after 3 years, in DM and non-DM patient respectively. CONCLUSIONS: Although there was a significant drop in mean fasting glucose after gastrectomy, not all patients experienced a drop in fasting glucose. Gastrectomy did not show a consistent association with glucose reduction in patients with and without diabetes, and in about half of the patients, fasting plasma glucose levels increased after gastrectomy. Therefore, bariatric surgery including gastrectomy needs to be performed with care in diabetes, and glucose monitoring including oral glucose tolerance tests should be done for assessing or prediction of the glucose state after gastric surgery in non-DM patients.

Dietary supplement use and its effect on nutrient intake in Korean adult population in the Korea National Health and Nutrition Examination Survey IV (2007-2009) data.

BACKGROUND/OBJECTIVES: Although there is an increasing trend of dietary supplement (DS) use, few researches have evaluated nutrient intake from DS. This study aimed to establish a nutrient database (NDB) for DS and estimate the effect of DS on total nutrient intake by Korean adults. SUBJECTS/METHODS: The NDB for DS was established using the label information of products reported in the Korea National Health and Nutrition Examination Survey (KNHANES) IV. Of the 16,031 participants who were ≥20 years old, 2053 products were reported as being taken by 5606 subjects. But nutrient composition could be identified by searching product name only in 1158 products consumed by 3844 subjects (DS users). Total nutrient intake of DS users was obtained by combining intakes from diet and DS. RESULTS: Dietary supplement use was higher in women, in middle-aged people and in those with higher education and low smoking and drinking preferences. Nutrients obtained from food were higher in DS users than in nonusers for most nutrients, particularly in women. When total nutrient intake was evaluated in DS users, the percentage of subjects whose intake was below the estimated average requirement for Koreans decreased for several vitamins and minerals, but the percentage of subjects whose intake was above the tolerable upper intake levels increased for vitamin A, vitamin C and iron. CONCLUSIONS: The newly developed NDB for DS will be an important resource for more accurate assessment of nutrient intake as well as evaluation of the relationship between nutrition and health. Further research is needed to update a more comprehensive NDB applicable to diverse populations.

Microsurgical skill assessment: toward skill-based surgical robotic control.

A surgical skill assessment system was developed to quantify microsurgical skills. Infrared optical makers, an inertial measurement unit, and strain gauges were mounted on tweezers to record surgical tasks. In preliminary experiments, the tool tip trajectory, acceleration, and applied force were measured and microsurgery videos were evaluated by three expert surgeons. The preliminary results indicated the feasibility of the system by showing the significant difference between unskilled and skilled surgeons.

Comparison of ramosetron with ondansetron for prevention of postoperative nausea and vomiting in patients undergoing gynaecological surgery.

BACKGROUND: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonist that reportedly has more potent antiemetic effects compared with other 5-HT(3) receptor antagonists. The purpose of this study was to evaluate the efficacy of ramosetron for the prevention of postoperative nausea and vomiting (PONV) with that of ondansetron or placebo in high-risk patients undergoing gynaecological surgery. METHODS: In this prospective, randomized, double-blinded, placebo-controlled study, 162 healthy patients who were undergoing gynaecological operation under general anaesthesia using sevoflurane were enrolled. Patients were divided into three groups: the ramosetron group (0.3 mg i.v.; n=54), the ondansetron group (8 mg i.v.; n=54), and the placebo group (normal saline i.v.; n=54). The treatments were given before the end of surgery. The incidence of PONV, severity of nausea, and the use of rescue antiemetic requirements during the first 24 h after surgery were evaluated. RESULTS: The incidence of nausea was lower in the ramosetron (50%) and ondansetron (44%) groups compared with the placebo group (69%) (P<0.05). In addition, the incidence of vomiting was lower in both the ramosetron (17%) and the ondansetron (20%) groups than in the placebo group (44%) during the first 24 h after surgery (P<0.05). The visual analogue scale score for nausea was also lower in the ramosetron and ondansetron groups compared with the placebo group (P<0.05). The proportion of patients requiring rescue antiemetics was significantly lower with ramosetron (15%) when compared with the placebo group (41%) during the 24 h after surgery (P<0.05). However, there were no significant differences in the incidence of nausea and vomiting, severity of nausea, and required rescue PONV between the ramosetron and the ondansetron groups. CONCLUSIONS: Ramosetron 0.3 mg i.v. was as effective as ondansetron 8 mg i.v. in decreasing the incidence of PONV and reducing nausea severity in female patients during the first 24 h after gynaecological surgery.

Inhibitory activity of Bifidobacterium longum HY8001 against Vero cytotoxin of Escherichia coli O157:H7.

Vero cytotoxin (VT)-producing Escherichia coli (VTEC), such as E. coli O157:H7, are emerging foodborne pathogens worldwide. VTs are associated with hemorrhagic colitis and hemolytic uremic syndrome in humans. Attachment of the B subunit of VTs to its receptor, globotriaosylceramide (Gb3), at gut epithelium is the primary step and, consequently, the A subunit of VTs inhibits protein synthesis in the target cell. Proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, up-regulate Gb3 expression, increase sensitivity to VTs, and enhance VT action in developing disease. Currently, there is a growing interest in probiotics, given the increasing occurrence of antibiotic-resistant bacteria. In particular, much work on bifidobacteria among probiotics, regarded as microorganisms targeted for technological and therapeutic applications, has been performed. In Korea, the neutralizing effect of the culture supernatant of Bifidobacterium longum HY8001, Korean isolate, against the VTs from E. coli O157:H7 was found. Therefore, this study focused on the raveling of the inhibitory effect of B. longum HY8001 against VTs, through the interference B subunit of VTs and Gb3 interaction. Mice were inoculated intragastrically with B. longum HY8001 culture supernatant before and after challenge with E. coli O157:H7. Control mice were inoculated intragastrically only with E. coli O157:H7. Cytokine, TNF-alpha, and IL-1beta levels in sera and expression of their mRNA were decreased, and expression of Gb3 in renal tubular epithelial cells was reduced in mice treated with B. longum HY8001 culture supernatant. In competitive enzyme-linked immunosorbent assays (ELISAs), the culture supernatant of B. longum HY8001 primarily binds VTs to interfere the VTs with Gb3 interaction. These results suggest that soluble substance(s) in B. longum HY8001 culture supernatant may have inhibitory activity on the expression of Gb3, VT-Gb3 interaction, or both. Further study should be done to elucidate the property of soluble substances in B. longum HY8001 culture supernatant.

Administration of prostaglandin E1 reduces post-operative hepatocellular damage and restores hepatic integrity in patients undergoing hepatectomy.

BACKGROUND/AIMS: The direct protective effects of prostaglandin E1 against hepatic dysfunction are unclear in recent studies. The aim of the present study was to investigate whether post-operative administration of prostaglandin E1 reduces serum concentrations of alpha-glutathione S-transferase, a new indicator of hepatocellular injury, in patients undergoing hepatectomy. METHODOLOGY: The subjects were 15 patients with hepatocellular carcinoma or hilar cholangiocarcinoma undergoing hepatectomy. Prostaglandin E1 was administered to 10 patients (PGE1 group) and was not administered to 5 patients (control group). Prostaglandin E1 was administered for 24 hours from noon on post-operative day 1 to noon on post-operative day 2. Serum concentrations of alpha-glutathione S-transferase, reduced glutathione, cyclic adenosine monophosphate, and total bilirubin, and the concentration of reduced glutathione in bile were measured post-operatively. RESULTS: The serum concentration of alpha-glutathione S-transferase was significantly lower and the serum bilirubin concentration was lower in the PGE1 group than in the control group. The serum concentrations of reduced glutathione and cyclic adenosine monophosphate were significantly higher in the PGE1 group than in the control group. Reduced glutathione in bile was higher in the PGE1 group than in the control group. CONCLUSIONS: The present results show that administration of prostaglandin E1 reduces hepatocellular injury and restores hepatic integrity, post-operatively, in patients undergoing hepatectomy.

Predicting survival and post-operative complications with Tc-GSA liver scintigraphy in hepatocellular carcinoma.

BACKGROUND/AIMS: Technetium-99m galactosyl human serum albumin is a novel liver scintigraphic agent. The aim of the present study was to examine whether liver scintigraphy with this agent could predict changes in hepatic function affecting survival in patients with inoperable hepatocellular carcinoma and liver cirrhosis. We also investigated whether the risk of major complications after hepatectomy for hepatocellular carcinoma could be assessed. METHODOLOGY: Liver scintigraphy was performed in 42 patients with inoperable hepatocellular carcinoma and cirrhosis and 40 patients undergoing hepatectomy. The ratio of liver to heart plus liver radioactivity 15 min after injection (LHL15) was calculated. RESULTS: The 1-year survival rates were higher in patients with higher LHL15: 100%, LHL15 > or = 0.91; 77.8%, 0.81 < or = LHL15 < or = 0.90; and 28.6%, LHL15 < or = 0.80. On multifactorial analysis, LHL15 significantly predicted the 1-year mortality rate in the 42 patients (p<0.001). Pre-operative LHL15 was significantly lower in 9 patients with major post-operative complications (0.88+/-0.02) than in 31 patients with uneventful courses or minor post-operative complications (0.93+/-0.01, p<0.001). CONCLUSIONS: Our results suggest that technetium-99m galactosyl human serum albumin liver scintigraphy is effective for predicting short-term survival in patients with inoperable HCC and cirrhosis and for assessing the risk of major complications after hepatectomy.

Prophylactic effect of Korean mistletoe (Viscum album coloratum) extract on tumor metastasis is mediated by enhancement of NK cell activity.

We here demonstrated the prophylactic effect of an extract (KM-110) from Viscum album coloratum, a Korean mistletoe, on tumor metastasis produced by highly metastatic tumor cells, colon 26-M3.1 carcinoma, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, using experimental models in mice. Intravenous (i.v.) administration of KM-110 (100 microg/mouse) 2 days before tumor inoculation significantly inhibited lung metastasis of B16-BL6 and colon 26-M3.1 cells, and liver and spleen metastasis of L5178Y-ML25 cells. The prophylactic effect of KM-110 on tumor metastasis was evident with various administration routes, i.e. subcutaneous, oral, intranasal as well as i.v., and was dependent upon the dose of KM-110 administered. Furthermore, mice given KM-110 (100 microg) 2 days before tumor inoculation showed significantly prolonged survival rates compared with the untreated mice. In a time course analysis of NK activity, i.v. administration of KM-110 (100 microg) significantly augmented NK cytotoxicity to Yac-a tumor cells from 1 to 3 days after KM-110 treatment. Furthermore, depletion NK cells by injection of rabbit anti-asialo GM1 serum completely abolished the inhibitory effect of KM-110 on lung metastasis of colon 26-M3.1 cells. These results suggest that KM-110 possesses immunopotentiating activity which enhances the host defense system against tumors, and that its prophylactic effect on tumor metastasis is mediated by NK cell activation.

Efficacy of preconditioning with N-acetylcysteine against reperfusion injury after prolonged cold ischaemia in rats liver in which glutathione had been reduced by buthionine sulphoximine.

OBJECTIVE: To investigate the ability of N-acetylcysteine (NAC) to prevent cold ischaemic-reperfusion injury and improve hepatic integrity in a glutathione-depleted condition. DESIGN: Open laboratory study. SETTING: University hospitals, Japan and France. MATERIALS: 40 male Wistar rats. INTERVENTIONS: To produce a glutathione-depleted liver, buthionine sulphoximine (BSO) was injected intraperitoneally 2 hours before either NAC or 5% dextrose was infused 15 minutes before the liver was harvested. We used an isolated perfused rat liver model that had undergone prolonged hypothermic ischaemia, cold-storage for 48 hours and reperfusion for 120 minutes. MAIN OUTCOME MEASURES: Concentrations of hepatic enzymes released into samples of perfusate, concentration of adenosine triphosphate in liver tissue, concentrations of reduced and oxidized glutathione in perfusate, and bile production. RESULTS: The concentrations of the hepatocellular enzymes and oxidised glutathione in the perfusate samples were significantly reduced in the NAC group compared with the 5% dextrose group. Bile production improved significantly in the NAC group compared with the 5% dextrose group. The concentration of reduced glutathione in liver tissue was not increased by NAC. CONCLUSION: In a glutathione-depleted liver NAC prevented hepatic injury and improved liver integrity after a cold ischaemic-reperfusion injury, by acting not as a substrate for glutathione synthesis but as a direct free radical scavenger.

Augmentation of mitochondrial reduced glutathione by S-adenosyl-L-methionine administration in ischemia-reperfusion injury of the rat steatotic liver induced by choline-methionine-deficient diet.

We examined whether warm ischemia-reperfusion (I/R) damage of the rat steatotic liver can be reduced by administration of S-adenosyl-L-methionine (SAMe). We examined the effect of SAMe on the mitochondrial reduced-glutathione (GSH) pool. Sixty minutes of partial left lobar vascular clamping followed by 2 h of reperfusion were employed for a model of hepatic warm ischemia. Either 5% dextrose or SAMe was injected intraperitoneally 2 h before I/R in steatotic rats (S-D5% or S-SAMe group). Serum liver enzyme concentrations 2 h after reperfusion were significantly lower in the S-SAMe group than in the S-D5% group. The cytosolic and mitochondrial GSH concentrations after I/R were significantly higher in the S-SAMe group than in the S-D5% group (p < 0.05). The cytosolic and mitochondrial oxidized-glutathione/GSH ratios after I/R were significantly greater in the S-D5% group than in the S-SAMe group (p < 0.01). The adenosine triphosphate concentration was higher in the S-SAMe group than in the S-D5% group (p = 0.0515). These results show that hepatocellular and mitochondrial oxidative stress after I/R in the steatotic liver can be reduced by administration of SAMe. The results also show that mitochondrial function and hepatocellular integrity can be restored by administration of SAMe in steatotic rats.

D-Erythroascorbic acid is an important antioxidant molecule in Saccharomyces cerevisiae.

D-Arabinono-1,4-lactone oxidase catalysing the final step of D-erythroascorbic acid biosynthesis was purified from the mitochondrial fraction of Saccharomyces cerevisiae. Based on the amino acid sequence analysis of the enzyme, an unknown open reading frame (ORF), YML086C, was identified as the ALO1 gene encoding the enzyme. The ORF of ALO1 encoded a polypeptide consisting of 526 amino acids with a calculated molecular mass of 59493Da. The deduced amino acid sequence of the enzyme shared 32% and 21% identity with that of L-gulono-1,4-lactone oxidase from rat and L-galactono-1,4-lactone dehydrogenase from cauliflower, respectively, and contained a putative transmembrane segment and a covalent FAD binding site. Blot hybridization analyses showed that a single copy of the gene was present in the yeast genome and that mRNA of the ALO1 gene was 1.8kb in size. In the alo1 mutants, D-erythroascorbic acid and the activity of D-arabinono-1,4-lactone oxidase could not be detected. The intracellular concentration of D-erythroascorbic acid and the enzyme activity increased up to 6.9-fold and 7.3-fold, respectively, in the transformant cells carrying ALO1 in multicopy plasmid. The alo1 mutants showed increased sensitivity towards oxidative stress, but overexpression of ALO1 made the cells more resistant to oxidative stress.

The effects of N-acetylcysteine and anti-intercellular adhesion molecule-1 monoclonal antibody against ischemia-reperfusion injury of the rat steatotic liver produced by a choline-methionine-deficient diet.

Abundant fat in the liver has been implicated in poor outcome after liver transplantation or liver surgery, but the reasons for this association are still unclear. The aim of the present study was to examine mechanisms that may be involved in hepatic dysfunction after ischemia-reperfusion (I/R) of the steatotic rat liver. Steatosis was produced by a choline-methionine-deficient (CMDD) diet. In the first experiment, isolated perfused rat livers, subjected to 24-hour cold storage followed by 120-minute reperfusion, were used to investigate hypothermic I/R injury of the steatotic rat liver. In the second experiment, livers were subjected to 60-minute partial left lobar vascular clamping to allow study of normothermic I/R injury. In the first experiment, compared with normal nonsteatotic liver, steatotic livers showed significantly greater injury, as assessed by amounts of hepatic enzymes released into the perfusate, bile production, the concentrations of reduced glutathione (GSH) in the perfusate, as well as in the livers themselves, and electron microscopic findings of sinusoidal microcirculatory injury. The addition of N-acetylcysteine (NAC), a precursor of glutathione, to the liver before cold storage significantly improved these parameters in steatotic livers. The second experiment showed that, compared with nonsteatotic livers, steatotic livers had lower concentrations of GSH and impaired rates of bile production. There was also evidence of increased oxidative stress in polymorphonuclear leukocytes (PMNLs) in liver or peripheral blood of rats with fatty livers. An anti-rat intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody inhibited neutrophil infiltration into pericentral sinusoids and improved these parameters in the steatotic rats. We conclude that sinusoidal microcirculatory injury is involved in hypothermic I/R injury, that oxidative stress produced by PMNLs is involved in normothermic I/R injury, and that NAC and anti-rat ICAM-1 monoclonal antibody restore liver integrity in I/R injury.