For the diagnosis of well-differentiated

HCC, F-18 fluorocholine for evaluation of phospholipid metabolism and C-11 acetate for evaluation of free fatty acid metabolism are useful in the diagnosis of that HCC. It is expected that the combination of these PET agents will enhance the diagnostic performance of FDG-PET for HCC in the future. The problem of a lack of anatomical information is being resolved with the development of the use of PET in combination with computed tomography or magnetic resonance imaging. For the problem of low resolution, PET devices using semiconductors have been developed. “
“Background and Aim:  Surgery is the standard treatment option for hepatocellular carcinoma (HCC) meeting the Milan criteria, defined as single HCC ≤ 5 cm in maximum diameter or up to three nodules ≤ 3 cm. However, favorable survival outcomes

have also been reported for these HCCs following radiofrequency ablation (RFA). Venetoclax molecular weight Methods:  We performed a systematic review to compare the results of hepatic resection and percutaneous RFA as a primary treatment option of HCC meeting the Milan criteria. Studies were identified by searching MEDLINE on PubMed, the Cochrane Library database and CANCERLIT using appropriate key words. Results:  In all six identified observational studies, there were no statistically significant differences in overall survival rates between the two treatment modalities. The results of two U0126 chemical structure randomized trials are controversial, while the power of these randomized trials is too limited to reach a reliable conclusion. In practice, the choice of treatment between surgery and RFA largely depends on the relationship between the local recurrence and perioperative mortality rates of HCC patients. Following RFA, local recurrence rates are low when a minimal safety margin ≥ 4–5 mm is achieved. A previous simulation study of overall survival for very early stage HCC, defined as an asymptomatic solitary small HCC ≤ 2 cm, showed that primary RFA with a 9% local recurrence rate is comparable to surgical resection with a

3% operative mortality rate. Conclusion:  Acquisition of a sufficient safety margin seems to Buspirone HCl be a critical factor before recommending wider application of RFA as primary treatment for HCCs that meet the Milan criteria. “
“Background and Aim:  Postinfectious irritable bowel syndrome (PI-IBS), which results from inflammation has been emphasized a lot recently. Dendritic cells (DCs) may contribute to intestinal mucosal immune activation in the pathogenesis of PI-IBS. This study tested the hypothesis that phenotype and function of intestinal lamina propria DCs (LPDCs) changed in the development of a PI-IBS mouse model. Methods:  Mice infected with Trichinella spiralis underwent abdominal withdrawal reflex (AWR) to evaluate visceral sensitivity. LPDCs were isolated and purified by intestine digestion and magnetic label-based technique.

6% after treatment ended. When SVR rates were examined with respect to fibrosis grade and regular drinking during critical periods (Table 7), SVR was higher only among patients who did not drink regularly prior to HCV diagnosis and had lower grade fibrosis. Thirty-four patients relapsed Selleckchem Dabrafenib after being clear of virus at the end of treatment; 14.7% reported drinking after treatment ended, compared with 10.7% among patients who did not relapse (P = 0.453). Early studies of alcohol consumption and outcomes of HCV treatment with interferon monotherapy in Japan12-14 and Italy15, 16 consistently indicated that heavy drinking was associated with significantly poorer

SVR rates. These studies were limited by small sample sizes, failure to control for adherence to antiviral therapy, and use of crude alcohol measures.

Nonetheless, they provided a rationale for excluding patients with a history of alcohol abuse from clinical trials of new antiviral therapy. Accordingly, few studies relating alcohol consumption to HCV treatment outcomes with combination interferon and ribavirin therapy have been conducted. Anand et buy VX-770 al.9 reported data from a multicenter study involving a select group of 726 veterans treated three times weekly with interferon-alpha and ribavirin. They found that drinking in the 12 months before treatment was significantly associated with failure to complete treatment (40% versus 26%; P = 0.0002) and a reduced SVR rate (14% versus 20%; P = 0.06). In a per-protocol analysis of patients who completed treatment, the negative effect of recent drinking on SVR rates disappeared (25% versus 23%). A study of patients treated with P/R in a university-affiliated outpatient clinic serving an inner city population found that a past history of consuming more than 30 g/day of ethanol was associated with significantly lower SVR rates.17 This finding was based on an intention-to-treat analysis, which included patients

who discontinued treatment early for reasons other than lack of an early virological response; it was noted that 46% of the sample (53 of 115) failed to complete treatment, and that past alcohol intake was not significantly Nintedanib (BIBF 1120) related to outcome in patients who completed treatment. Given the relatively high SVR rates obtained in our cohort, we expected moderate drinking patterns to predominate in our patients. Therefore, it came as a surprise to find that over 60% had a pretreatment alcohol intake over 100 kg, an amount above which rates of alcoholic liver disease begin to increase,18 and over 15% reported drinking more than 10 times this amount. A key difference between our patients and those previously studied is that only 14% discontinued treatment, and discontinuation was related to pretreatment alcohol intake only in noncompliant patients, who made up less than 2% of the cohort and were mainly limited to patients whose pretreatment alcohol intake was over 1,000 kg.

Conclusions: The minor genotype of MICA rs2596542 correlates with an increased risk of HCC development, particularly in older patients. Disclosures: Akihiro Tamori – Grant/Research Support: MSD The following people have nothing to disclose: Hoang Hai, Kanako Yoshida, Atsushi Hagihara, Etsushi Kawamura, Hideki Fujii, Sawako K. Uchida, Shuji Iwai, Hiroyasu Morikawa, Masaru Enomoto, Yoshiki Murakami, Thuy T. Le, Norifumi Kawada Introduction. Several trials, especially in chronic hepatitis C, rely cirrhosis diagnosis selleckchem on a single cut-off of non-invasive test(s). False positives are generally thought to be fibrosis stage(s) close to cirrhosis. Yet, these statements are

based on any recommendation. Therefore, we evaluated predictive values for cirrhosis of available non-invasive tests including a detailed fibrosis classification. Methods. All 1735 patients had chronic hepatitis C and liver biopsy with Metavir fibrosis (F) staging. We evaluated negative (NPV) and positive

(PPV) predictive values of tests considering either only the F4 class or all the classes including F4 (e. g. F3/F4) called Fx/4. The highest value of NPV and PPV determined the choice of fibrosis class cut-off and non-invasive test. In population #1 including 1056 patients, we compared blood tests: Fibrotest, FibroMeter and CirrhoMeter. In population #2 including 679 patients, we compared previous blood tests, liver stiffness JNK activity (Fibroscan) and their combination (CombiMeter). Other characteristics were evaluated: F distribution,

morphometry, markers of liver function or portal hypertension. Results (table). Population #1: considering a cirrhosis trial, the optimal choice relies on the cut-off of CirrhoMeter F4 class since its PPV provides a high inclusion rate of cirrhosis (88%) vs. a rate of only 37% with Fibrotest (35% of pts being F2 or F1 or F0), but at the expense of a higher number of patients to screen. Considering trials excluding cirrhosis, the optimal choice relies on the cut-off of CirrhoMeter Fx/4 classes since its NPV provides a low inclusion rate of cirrhosis (1%) vs. a rate of 4% with Fibrotest, but at the expense of a higher number of patients to screen. Population #2: results validated the best PPV of CirrhoMeter F4 class (89%). They also validated an excellent Roflumilast NPV of Fx/4 classes in all single tests (NPV=97%) with, nevertheless, a small advantage for the test combination (NPV: 98%). Conclusion. A blood test designed for cirrhosis can affirm (88-89% prediction) or exclude (97-99% prediction) cirrhosis by using different cut-offs of a detailed fibrosis classification. This can be easily applied in trials whereas, in clinical practice, another examination might be required in the grey zone between the two cut-offs. Certain criteria induce the inappropriate inclusion of around 2/3 of patients.

3 To date, molecular targeted therapy has shown promise for the treatment of advanced HCC,4 but it is unclear how these genetic changes cause the clinical characteristics observed in individual HCC patients.

Histone deacetylases (HDACs) are often recruited by corepressors or multiprotein transcriptional complexes to gene promoters, whereby they regulate transcription by way of chromatin modification without directly see more binding to DNA.5 There are 18 encoded human HDACs, which are classified as: class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10), class III (SIRT1-7), and class IV (HDAC11) enzymes,6 and evidence indicates that both histone acetyltransferases (HATs) and HDACs are involved in cell proliferation, differentiation, and cell cycle regulation.7 In addition, it has been reported that the pathological activity and deregulation of HDACs can lead to several diseases, such as cancer, immunological disturbances, and muscular dystrophy.8 However, despite the involvement of HDACs in the development of cancer, the specific roles fulfilled by individual HDACs in the regulation of cancer development remain unclear. HDAC6 is a member of the class IIb family of HDACs and acts as a cytoplasmic deacetylase that associates with microtubules and deacetylates α-tubulin.9 Microtubule-associated HDAC6 is a critical component of the lysosomal STA-9090 clinical trial protein degradation

pathway, and it has been recently suggested that HDAC6 plays an important role in the eventual clearance of aggresomes, which implies a functional connection between autophagic signaling and control of the fusion of autophagosomes and lysosomes associated with the control of autophagy by way of the recruitment of cortactin-dependent, actin-remodeling machinery to ubiquitinated protein aggregates.10 On the other hand, HDAC6 has been shown to be involved in carcinogenic transformation and to modulate the epithelial-mesenchymal transition in several cancers by way of the regulations of several critical cellular functions,11,

12 and accumulating evidence indicates that the expression of HDAC6 is correlated with oncogenic transformation, anchorage-independent proliferation, Cepharanthine and tumor aggressiveness. Furthermore, it has been shown that the inactivation of HDAC6 by genetic ablation or by specific short small interfering RNA (siRNA) increases resistance to oncogenic transformation and decreases the growth of human breast and ovarian cancer cell lines in vitro and in vivo.13, 14 Therefore, the up-regulation of HDAC6 in diverse tumors and cell lines suggests that HDAC6 plays an important role in cancer. However, our previous transcriptome analysis on multistep hepatopathogenesis suggested the down-regulation of HDAC6 in overt HCC as compared with noncancerous tissues, and our initial analysis of HDAC6 in human HCC tissues indicated the loss of HDAC6 expression in HCCs.

3 To date, molecular targeted therapy has shown promise for the treatment of advanced HCC,4 but it is unclear how these genetic changes cause the clinical characteristics observed in individual HCC patients.

Histone deacetylases (HDACs) are often recruited by corepressors or multiprotein transcriptional complexes to gene promoters, whereby they regulate transcription by way of chromatin modification without directly Selleckchem Romidepsin binding to DNA.5 There are 18 encoded human HDACs, which are classified as: class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10), class III (SIRT1-7), and class IV (HDAC11) enzymes,6 and evidence indicates that both histone acetyltransferases (HATs) and HDACs are involved in cell proliferation, differentiation, and cell cycle regulation.7 In addition, it has been reported that the pathological activity and deregulation of HDACs can lead to several diseases, such as cancer, immunological disturbances, and muscular dystrophy.8 However, despite the involvement of HDACs in the development of cancer, the specific roles fulfilled by individual HDACs in the regulation of cancer development remain unclear. HDAC6 is a member of the class IIb family of HDACs and acts as a cytoplasmic deacetylase that associates with microtubules and deacetylates α-tubulin.9 Microtubule-associated HDAC6 is a critical component of the lysosomal Nivolumab protein degradation

pathway, and it has been recently suggested that HDAC6 plays an important role in the eventual clearance of aggresomes, which implies a functional connection between autophagic signaling and control of the fusion of autophagosomes and lysosomes associated with the control of autophagy by way of the recruitment of cortactin-dependent, actin-remodeling machinery to ubiquitinated protein aggregates.10 On the other hand, HDAC6 has been shown to be involved in carcinogenic transformation and to modulate the epithelial-mesenchymal transition in several cancers by way of the regulations of several critical cellular functions,11,

12 and accumulating evidence indicates that the expression of HDAC6 is correlated with oncogenic transformation, anchorage-independent proliferation, Tyrosine-protein kinase BLK and tumor aggressiveness. Furthermore, it has been shown that the inactivation of HDAC6 by genetic ablation or by specific short small interfering RNA (siRNA) increases resistance to oncogenic transformation and decreases the growth of human breast and ovarian cancer cell lines in vitro and in vivo.13, 14 Therefore, the up-regulation of HDAC6 in diverse tumors and cell lines suggests that HDAC6 plays an important role in cancer. However, our previous transcriptome analysis on multistep hepatopathogenesis suggested the down-regulation of HDAC6 in overt HCC as compared with noncancerous tissues, and our initial analysis of HDAC6 in human HCC tissues indicated the loss of HDAC6 expression in HCCs.

3 To date, molecular targeted therapy has shown promise for the treatment of advanced HCC,4 but it is unclear how these genetic changes cause the clinical characteristics observed in individual HCC patients.

Histone deacetylases (HDACs) are often recruited by corepressors or multiprotein transcriptional complexes to gene promoters, whereby they regulate transcription by way of chromatin modification without directly learn more binding to DNA.5 There are 18 encoded human HDACs, which are classified as: class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10), class III (SIRT1-7), and class IV (HDAC11) enzymes,6 and evidence indicates that both histone acetyltransferases (HATs) and HDACs are involved in cell proliferation, differentiation, and cell cycle regulation.7 In addition, it has been reported that the pathological activity and deregulation of HDACs can lead to several diseases, such as cancer, immunological disturbances, and muscular dystrophy.8 However, despite the involvement of HDACs in the development of cancer, the specific roles fulfilled by individual HDACs in the regulation of cancer development remain unclear. HDAC6 is a member of the class IIb family of HDACs and acts as a cytoplasmic deacetylase that associates with microtubules and deacetylates α-tubulin.9 Microtubule-associated HDAC6 is a critical component of the lysosomal Tamoxifen research buy protein degradation

pathway, and it has been recently suggested that HDAC6 plays an important role in the eventual clearance of aggresomes, which implies a functional connection between autophagic signaling and control of the fusion of autophagosomes and lysosomes associated with the control of autophagy by way of the recruitment of cortactin-dependent, actin-remodeling machinery to ubiquitinated protein aggregates.10 On the other hand, HDAC6 has been shown to be involved in carcinogenic transformation and to modulate the epithelial-mesenchymal transition in several cancers by way of the regulations of several critical cellular functions,11,

12 and accumulating evidence indicates that the expression of HDAC6 is correlated with oncogenic transformation, anchorage-independent proliferation, Bay 11-7085 and tumor aggressiveness. Furthermore, it has been shown that the inactivation of HDAC6 by genetic ablation or by specific short small interfering RNA (siRNA) increases resistance to oncogenic transformation and decreases the growth of human breast and ovarian cancer cell lines in vitro and in vivo.13, 14 Therefore, the up-regulation of HDAC6 in diverse tumors and cell lines suggests that HDAC6 plays an important role in cancer. However, our previous transcriptome analysis on multistep hepatopathogenesis suggested the down-regulation of HDAC6 in overt HCC as compared with noncancerous tissues, and our initial analysis of HDAC6 in human HCC tissues indicated the loss of HDAC6 expression in HCCs.

WE ARE VERY grateful to the physicians, veterinarians and hunters throughout Japan who kindly supplied us with serum and/or liver specimens for the serological and molecular analyses of HEV infection. This study was supported in part by grants from the Ministry of Health, Labor and Welfare of Japan, and from the Ministry of Education, Culture, Sports, Science and Technology of Japan. “
“Cadherins mediate cell-cell adhesion and catenin (ctn)-related signaling pathways.

Liver fibrosis is accompanied by the loss of E-cadherin (ECAD), which promotes the process of epithelial-mesenchymal transition. Currently, Ferroptosis phosphorylation no information is available about the inhibitory role of ECAD in hepatic stellate cell activation. Because of ECAD’s potential for inhibiting the induction of transforming growth factor β1 (TGFβ1), we investigated whether ECAD overexpression prevents TGFβ1 gene induction; we also examined what the molecular basis could be. Forced expression of ECAD decreased α-smooth muscle actin and vimentin levels and caused decreases in the constitutive and inducible expression of the TGFβ1 gene and its downstream

genes. ECAD overexpression decreased Smad3 phosphorylation, weakly decreased Smad2 phosphorylation, and thus inhibited Smad reporter activity induced by either treatment with TGFβ1 or Smad3 overexpression. Overexpression of a dominant negative mutant of ras homolog gene family A (RhoA) diminished the ability of TGFβ1 to elicit its own http://www.selleckchem.com/products/SB-203580.html gene induction. Consistently, transfection with a constitutively active mutant of RhoA reversed the inhibition of TGFβ1-inducible or Smad3-inducible reporter activity by ECAD. Studies using the mutant constructs of ECAD revealed that the p120-ctn binding domain of ECAD was responsible for TGFβ1 repression. Consistently, ECAD was capable of binding p120-ctn, which recruited RhoA; this prevented TGFβ1 from increasing Staurosporine cost RhoA-mediated Smad3 phosphorylation.

In the liver samples of patients with mild or severe fibrosis, ECAD expression reciprocally correlated with the severity of fibrosis. Conclusion: Our results demonstrate that ECAD inhibits Smad3/2 phosphorylation by recruiting RhoA to p120-ctn at the p120-ctn binding domain, whereas the loss of ECAD due to cadherin switching promotes the up-regulation of TGFβ1 and its target genes, and facilitates liver fibrosis. (HEPATOLOGY 2010.) E-cadherin (ECAD), a transmembrane glycoprotein that mediates adherens junctions, is developmentally restricted to polarized epithelial cells.1, 2 Repeated extracellular domains of ECAD are responsible for binding cells to neighboring ones and maintaining the structural integrity and polarization of epithelia. ECAD also regulates signaling pathways through the intracellular catenin (ctn) binding domains.

To prevent postpartum haemorrhage after delivery, women LBH589 solubility dmso routinely receive oxytocin,

which also causes fluid retention. Administration of DDAVP, combined with litres of fluids and oxytocin, may result in life-threatening hyponatraemia [70]. A single dose of DDAVP immediately prior to epidural catheter placement in labour, however, has not been associated with adverse events [71]. Among the published series of VWD in pregnancy there are multiple cases of postpartum haemorrhage that occurred despite prophylaxis [18]. In a review of published cases of women with VWD who experienced postpartum haemorrhage, Roque et al. [72] determined that the average time of haemorrhage was 15.7 ± 5.2 days after delivery. The implication is that women with bleeding disorders may require more frequent evaluation. Thus, weekly contact is suggested during the postpartum period [73]. Prophylaxis, when indicated, may be required for two or more weeks. More data are required to determine Pirfenidone molecular weight optimal length of prophylaxis. Data on the management of women with bleeding disorders are hampered by a lack of randomized trials, case-control studies or even large case series. No one centre sees a large

number of patients. Severe bleeding disorders are rare and women with milder disease may not come to the attention of a haemostasis centre or even be diagnosed. Funding for studies is limited. In the absence of strong evidence to direct

practice, government agencies and haemophilia organizations have developed consensus guidelines. There are at least nine sets of guidelines published by the government agencies or haemophilia organizations that specifically address women with bleeding disorders. The guidelines were reviewed and summarized in 2009 and found to be remarkably congruent [74]. The good news is that there Forskolin in vivo is consensus regarding many of the issues pertaining to the management of women with bleeding disorders. “
“Summary.  The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors – perceived by the immune system as danger signals – which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB).

Based on models of migraine pathology, several inflammatory molecules including protons are thought to facilitate sensitization

and activation of trigeminal nociceptive neurons and stimulate CGRP secretion. Despite the reported efficacy of triptans NVP-BGJ398 research buy and onabotulinumtoxinA to treat acute and chronic migraine, respectively, a substantial number of migraineurs do not get adequate relief with these therapies. A possible explanation is that triptans and onabotulinumtoxinA are not able to block proton-mediated CGRP secretion. Methods.— CGRP secretion from cultured primary trigeminal ganglia neurons was quantitated by radioimmunoassay while intracellular calcium and sodium levels were measured in neurons via live cell imaging using Fura-2

AM and SBFI AM, respectively. The expression of acid-sensing ion channel 3 (ASIC3) was determined by immunocytochemistry and Western blot analysis. In addition, the involvement of ASICs in www.selleckchem.com/products/Bortezomib.html mediating proton stimulation of CGRP was investigated using the potent and selective ASIC3 inhibitor APETx2. Results.— While KCl caused a significant increase in CGRP secretion that was significantly repressed by treatment with ethylene glycol tetraacetic acid (EGTA), onabotulinumtoxinA, and rizatriptan, the stimulatory effect of protons (pH 5.5) was not suppressed by EGTA, onabotulinumtoxinA, or rizatriptan. In addition, while KCl caused a transient increase in intracellular calcium levels that was blocked by EGTA, no appreciable change in calcium levels was observed with proton treatment. However,

protons did significantly increase the intracellular level of sodium ions. Under our culture conditions, ASIC3 was shown to be expressed in most trigeminal ganglion neurons. Importantly, proton stimulation of CGRP secretion was repressed by pretreatment with the ASIC3 inhibitor APETx2, but not the transient receptor potential vanilloid-1 antagonist capsazepine. Conclusions.— Our findings provide evidence that proton regulated release of CGRP from trigeminal neurons utilizes a different mechanism than the calcium and synaptosomal-associated protein 25-dependent pathways that are inhibited by the antimigraine therapies, rizatriptan and onabotulinumtoxinA. “
“Objective.— To examine total Guanylate cyclase 2C migraine freedom (TMF), defined as pain freedom and absence of associated symptoms, using rizatriptan clinical trial data and to explore advantages of TMF as a single primary composite efficacy endpoint. Background.— The FDA has set a higher regulatory hurdle for registration of new migraine agents requiring both pain freedom (or relief) and absence of each associated symptom (phonophobia, photophobia, and nausea). Methods.— Twelve studies representing phase III + efficacy/safety studies of rizatriptan 10 mg in adults treating migraine were included in the meta-analysis.

The frequency of antigen-specific ASC was calculated as a percentage of total IgG-producing cells. The

limit of detection (LD) was found to be three spots per well. These three spots were used to calculate the LD as a percentage of total spots obtained for IgG-producing cells for each individual patient. We set up an in vitro culture system that is suitable for studying the regulation of FVIII-specific memory B cells [17,18]. For this purpose, we obtained spleen cells from haemophilic mice treated with human FVIII and depleted these spleen cells of CD138+ ASC. Thereby, we generated a CD138− spleen cell population that did not contain any anti-FVIII ASC (Fig. 1) but contained FVIII-specific memory B, T cells and other cells. When we stimulated this CD138− cell mixture with human FVIII, FVIII-specific memory B cells were re-stimulated and differentiated into Palbociclib molecular weight anti-FVIII ASC that could be detected as soon as 3 days after re-stimulation (Fig. 1) [17]. The maximum of newly formed anti-FVIII ASC was observed 6 days PF-01367338 in vitro after re-stimulation (Fig. 1) [17]. In further experiments, we found that the re-stimulation of FVIII-specific memory B cells in our in vitro culture system

strictly depended on the presence of activated T cells [17]. Furthermore, a direct cell-to-cell contact between FVIII-specific memory B cells and activated T cells was required [17]. Based on our finding that activated T cells are required to re-stimulate FVIII-specific memory B cells in our in vitro culture system, Paclitaxel datasheet we wanted to identify the specific co-stimulatory interactions that would be necessary for this process. Furthermore, we were interested to find out whether blocking essential co-stimulatory interactions would prevent the re-stimulation of FVIII-specific memory B cells. We added blocking antibodies against CD40L, CD80 (B7-1), CD86 (B7-2), ICOSL or recombinant competitor proteins (mICOS/Fc, mCTLA-4/Fc) to the CD138− spleen cell cultures immediately before re-stimulation with FVIII to study the importance of the relevant ligand

receptor pairs. The blockade of B7-CD28 or CD40-CD40L interactions significantly inhibited the re-stimulation of FVIII-specific memory B cells (Fig. 2) [17]. Both CD80 (B7-1) and CD86 (B7-2) contributed to the required co-stimulatory interactions with CD28. Blockade of both molecules prevented the re-stimulation of memory cells almost completely, whereas the blockade of only one of the two molecules resulted in a partial blockade (Fig. 2) [17]. The negative control antibodies and human IgG1 (negative control for mCTLA-4/Fc) did not show any effect. In contrast to CD40-CD40L and B7-CD28 interactions, ICOS-ICOSL interactions did not contribute to the re-stimulation of FVIII-specific memory cells. Neither the addition of a blocking antibody against ICOSL nor the use of a recombinant competitor protein (mICOS/Fc) resulted in a significant alteration in the re-stimulation of memory B cells (Fig. 2) [17].