Dates of death were obtained from the Danish Civil Registration S

Dates of death were obtained from the Danish Civil Registration System, which is continuously updated with dates of birth, death, and emigration.22 Causes of death were ascertained from the Danish Cause of Death Registry, with review of registry data to determine whether deaths were from cirrhosis or other causes. Death from liver failure, variceal bleeding,

bacterial infection, or hepatocellular carcinoma counted as death from cirrhosis. Data linkage across data sources was made possible by the find more unique personal identifier issued to all Danish citizens at birth or immigration and used in all national databases and record systems. At the time of inclusion into the study cohort, patients with alcoholic cirrhosis were classified into five categories

according to the presence and type of cirrhosis complications: no complications; ascites alone; variceal bleeding alone; ascites and variceal bleeding; hepatic encephalopathy with or without ascites and variceal bleeding. Patients who developed complications during follow-up were PI3K inhibitor cancer reclassified into another category if appropriate. Based on our clinical experience and a previous Danish study,23 we assumed that a given complication carried the same prognosis whether it had been present at the time of cirrhosis diagnosis or developed later. Racecadotril In all analyses follow-up ended at death or at censoring at the end of follow-up, on 31 August 2006. Analyses were conducted separately for the five complication categories and were based on the Aalen-Johansen estimator of the probability of having died or being in a particular category of cirrhosis complications at a particular point in time during follow-up.24, 25 Ninety-five percent

confidence intervals were bootstrapped. We conducted three types of analyses which differed in the handling of complications during follow-up. In the first analysis complications were ignored, hence the Aalen-Johansen method was simplified to a Kaplan-Meier analysis yielding the cumulative mortality and the median survival time, i.e., the time to reach a cumulative mortality of 50%. In the second analysis complications were taken into account, but follow-up continued when they developed. On that basis we estimated the distribution of cirrhosis complication categories after 1 and 5 years of follow-up using the following categorization: alive without more complications; alive with more complications; dead without more complications; and dead with more complications. In the third analysis follow-up ended whenever complications developed, whereby the Aalen-Johansen method amounted to estimating the 1-and 5-year cumulative incidence (i.e., risk) of complications or death as competing events.

8 In contrast, administration of exogenous Bmp6 to mice increased

8 In contrast, administration of exogenous Bmp6 to mice increased hepatic Hamp expression and reduced both serum iron and transferrin saturation (TS).2, 9 Liver-specific Smad4 null mice also developed iron overload

and impaired Bmp signaling, suppressing hepcidin production.4 Taken together, these observations strongly support VX-765 mw BMP6 as the key endogenous regulator of hepcidin synthesis and iron metabolism in vivo. Recently, it was shown that inhibitory SMAD7 tempers HAMP expression by blocking the interaction of SMAD1/5/8 with SMAD4.10 TFR2 and HFE are thought to act as iron-sensing molecules to receive signals from circulating holotransferrin to modulate hepatic HAMP expression. TFR2 is a strong candidate as a sensor of serum TS, because it binds holotransferrin and undergoes posttranslational stabilization.11 As TS increases, HFE dissociates from TFR1 and binds to TFR2 to possibly convey the necessary signal downstream to stimulate hepcidin synthesis.12, 13 Some studies support the premise that TFR2 and HFE interact with the BMP6–SMAD pathway, because this signaling pathway is impaired in Tfr2 and/or Hfe null mice9, 14-16 as well as in subjects with HFE-associated HH,17, 18 whereas others report no interaction.5 TFR2 and HFE may also signal independently of

each other, because disruption of both Tfr2 and Hfe in mice causes a more severe iron overload phenotype.16 TFR2 and HFE, however, are likely to modulate SMAD signaling downstream Inhibitor Library price of BMP6 due to their redundancies in BMP6 transcription.7, 14, 15 Holotransferrin, through TFR2 and HFE signaling, may also regulate hepcidin by activating the extracellular signal-regulated kinases 1 and 2 and mitogen-activated protein kinases (ERK1/2–MAPK) pathway16, 19, 20 and interact with the BMP–SMAD pathway.16, 19 The interaction between

BMP–SMAD and ERK–MAPK pathways is not fully understood. The current study by Corradini et al.21 adds to an actively expanding body of work to unravel the complexities of hepcidin regulation by iron. Iron-dependent ADP ribosylation factor regulation of hepcidin appears to involve both liver iron and circulating iron levels.7, 21 The modulation of hepcidin expression by liver iron is likely to be mediated through the BMP6–SMAD signaling pathway, whereas regulation by serum TS is mediated by TFR2 and HFE signaling, although the latter mechanism remains poorly defined. Corradini et al.21 show that, in a setting where there was a sudden surge in circulating iron levels with unaltered liver iron concentration (LIC), hepcidin responded according to the changes in serum TS. Mice administered 2 mg/kg iron (through oral gavage) had increased serum iron and TS levels after 1 hour of iron dosing, which returned to baseline levels by 8-24 hours, whereas LIC was unchanged over 24 hours.

No PC-deficient parents had experienced thromboembolism Of the 1

No PC-deficient parents had experienced thromboembolism. Of the 18 patients with aPC therapy, two died and eight

evaluable survivors had neurological sequelae. This first comprehensive study of paediatric PC deficiency suggested that perinatal ICTH was the major presentation, occurring earlier than neonatal PF. PC nagoya was prevalent in paediatric, but not adult, patients in Japan. Early maternal screening and optimal PC therapy are required for newborns at risk of PC deficiency. “
“Summary.  The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Memory B cells play an essential role in maintaining established antibody responses. Upon re-exposure to the same antigen, they are rapidly re-stimulated to proliferate and differentiate into antibody-secreting U0126 manufacturer plasma cells (ASC) that secrete high-affinity antibodies. It is, therefore, reasonable to believe that memory B cells have to be eradicated or inactivated for immune tolerance induction therapy to be successful in patients with haemophilia A and FVIII inhibitors. The aim of our studies was the development of strategies to prevent FVIII-specific memory B cells from becoming re-stimulated.

We established a 6-day in vitro culture system that enabled us to study the regulation of FVIII-specific murine memory-B-cell re-stimulation. We tested the impact of the blockade of co-stimulatory interactions, of different concentrations Rutecarpine of FVIII and of ligands for toll-like receptors (TLR). Talazoparib The blockade of B7-CD28 and CD40-CD40 ligand interactions prevented FVIII-specific murine memory B cells from becoming re-stimulated by FVIII in vitro and in vivo. Furthermore, high concentrations of FVIII blocked re-stimulation of FVIII-specific murine memory B cells. Triggering of TLR7 amplified re-stimulation

by low concentrations of FVIII and prevented blockade by high concentrations of FVIII. We conclude that we defined modulators that either amplify or inhibit the re-stimulation of FVIII-specific murine memory B cells. Currently, we are investigating whether the same modulators operate in patients with haemophilia A and FVIII inhibitors. The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and induce long-lasting immune tolerance [1–4]. Although this therapeutic approach was introduced by Dr Brackmann and co-workers more than 30 years ago [1], little is known about the immunological mechanisms that cause the down-modulation of FVIII-specific immune responses and the induction of long-lasting immune tolerance against FVIII. Memory B cells play an essential role in maintaining established antibody responses.

The real novelty and probably the most important finding of this

The real novelty and probably the most important finding of this study is the association between serum vitamin A deficiency and the condition of nonresponse to antiviral therapy, suggesting that vitamin A could be an important Rapamycin mw and modifiable factor interfering with IFN sensitivity in patients with chronic hepatitis C. This finding, together with the data suggesting an antiviral activity against HCV of ATRA, suggests that vitamin A supplementation and normalization of its serum levels, before antiviral treatment, could enhance

the responsiveness to INF-based antiviral therapy. These considerations seem to confirm those derived from in vitro experiments that provided evidence of a pivotal role of retinol in enhancing the expression of IFN receptor and IFN signaling, linking vitamin A deficiency Peptide 17 molecular weight to IFN unresponsiveness. The fact that vitamin A and vitamin D serum levels are not reciprocally influenced suggests that they can exert an additive and probably synergistic effect on viral response. Indeed, the analysis showed that a concomitant vitamin A and D deficiency strongly impairs the responsiveness to antiviral therapy and that its impact is not so far from that exerted by IL-28B polymorphisms. The major and obvious

difference is that, instead of IL-28B polymorphisms, vitamins serum levels might be modified. Moreover, it is important to note that a strong additive effect in determining nonresponse was observed in patients with concomitant carriage of the IL-28B T/* genotype and vitamin A serum levels ≤100 ng/mL. A possible

concern in terms of the use of vitamin A supplementation in clinical practice is represented by its possible hepatotoxicity.22 However, the experiences concerning the use of polyprenoic acid, a synthetic vitamin others A derivate, in the prophylaxis of HCC in patients with chronic viral hepatitis23 and the study by Bocher et al.9 did not support this assumption. The main limitations of the present study lie in its retrospective design and in the lack of data concerning the dietary intake of both vitamin A and D. It is conceivable that vitamin D serum levels could be greatly influenced by the season, since sunlight exposure is recognized as a key factor in determining vitamin D synthesis. Nevertheless, it cannot be excluded that season-related dietary variations could influence vitamin A intake and serum levels. Nevertheless, the multicenter design of the study supported the external validation of data that have been confirmed in each center. In conclusion, a high percentage of patients with chronic HCV infection presented serum vitamin A deficiency. This condition is strongly associated with nonresponse to antiviral therapy, suggesting that vitamin A serum levels could modulate the responsiveness to IFN-based antiviral therapy.


“A 66-year old man presented with several months of weight


“A 66-year old man presented with several months of weight loss. He denied any abdominal pain or change in bowel habits. On physical examination he was not clinically anaemic or jaundiced. He did exhibit multiple distinctive skin lesions (Figure 1A). Imaging of the chest and abdomen showed no obvious abnormalities. He underwent an upper and lower endoscopy to exclude an underlying GS 1101 gastrointestinal malignancy. A 1.5–2cm tumour was noted in the duodenum several centimetres distal to the ampulla of Vater (Figure 1B). Attempt at endoscopic

excision failed. Biopsy of the lesion was however diagnostic. The patient had an uncomplicated local duodenal resection. He was tumour free at 12 months follow-up. Numerous neurofibromas were noted on the patient’s trunk and abdomen. A café au-lait spot, was also seen. The findings are suggestive of neurofibromatosis-type 1 (NF1). Also known as von Recklighausen’s disease, the condition is named after Freidrich von Recklinghausen who first recognized the tumours that characterize the

disease in 1882. This is an autosomal dominant condition with an incidence of 1 in 3000 births. The condition shows near 100% penetrance but has variable expression. The genetic linkage has been localised to chromosome 17 (17q11.2 locus) coding for the protein, neurofibromin, selleck chemicals llc which has a tumour suppressor function. The periampullary lesion in the duodenum was typical of a carcinoid tumour. (Figure 2A) Less commonly, a neurofibroma may occur in the periampullary region in patients with NF1. Carcinoid tumours of the ampulla and periampullary region are more common in patients with NF1. The majority of these tumours are clinically non-functional, despite increased somatostatin production being frequently noted in tumours of patients with NF1. In addition Rebamipide to neurofibromas that are typical of NF1, phaeochromytoma can occur in up to 5% of patients. Malignant

gliomas are found in approximately 2% of cases and small intestinal gastrointestinal stromal tumours (GISTs) in about 7% of these patients, but rarely in a periampullary location. In children, there is an association of juvenile chronic myeloid leukaemia with NF1. Microscopically in well differentiated tumours, there is a proliferation of uniform, small, bland polygonal cells with finely clumped chromatin. The cells are arranged in a variety of architectural patterns, including insular, trabecular and acinar. The diagnosis is confirmed by immunohistochemically, as they stain positively for synaptophysin and chromogranin. (Figure 2B–D). In cases of well differentiated tumours, even with distant spread, 5-year survival of over 50% is reported. Contributed by “
“A 62-year-old man was admitted because of recurrent abdominal pain. He had been taking ibuprofen 400 mg/day for 3 years because of headache. Laboratory findings showed no abnormalities. H.

Our culture and field observations indicate that there is a previ

Our culture and field observations indicate that there is a previously unrecognized stage in the life cycle of P. antarctica G. Karst. This stage comprises nonmotile cells that Epigenetics Compound Library range in size from ∼4.2 to 9.8 μm in diameter and form aggregates in which interstitial spaces between cells are small or absent. The aggregates (hereafter called attached aggregates, AAs) adhere to available surfaces. In field samples, small AAs, surrounded by a colony skin, adopt an epiphytic lifestyle and adhere in most cases to setae or spines of diatoms. These AAs, either directly or via other life stages, produce the colonial life stage. Culture studies indicate that bloom-forming, colonial stages release flagellates (microzoospores)

that fuse and form AAs, which can proliferate on the bottom of culture vessels and can eventually reform free-floating colonies. We propose that these AAs are a new stage in the

life cycle of P. antarctica, which we believe to be the zygote, thus documenting sexual reproduction in this species for the first time. “
“Chroococcidiopsis Geitler (Geitler 1933) is a genus of cyanobacteria containing desiccation and radiation resistant strains. Members of the genus live in habitats ranging from hot and cold deserts to fresh and saltwater environments. Morphology and cell division pattern have historically been used to define the genus. To better understand the evolution and ability of the Chroococcidiopsis genus to survive Metabolism inhibitor in diverse environments we investigated how salt tolerance varies among 15 strains previously isolated from different locations, and if salt tolerant strains are monophyletic to those isolated from freshwater and land environments. Four markers were sequenced from these 15 strains, the 16S rRNA, rbcL, desC1, and gltX

genes. Phylogenetic trees were generated which identified a distinct clade of salt-tolerant strains. This study demonstrates that the genus is Paclitaxel cost polyphyletic based on saltwater and freshwater phenotypes. To understand the resistance to salt in more details, the strains were grown on a range of sea salt concentrations which demonstrated that the freshwater strains were salt-intolerant whilst the saltwater strains required salt for growth. This study shows an increased resolution of the phylogeny of Chroococcidiopsis and provides further evidence that the genus is polyphyletic and should be reclassified to improve clarity in the literature. “
“As the process of ocean acidification alters seawater carbon chemistry, physiological processes such as skeletal accretion are expected to become more difficult for calcifying organisms. The crustose coralline red algae (Corallinales, Rhodophyta) form an important guild of calcifying primary producers in the temperate Northeast Pacific. The morphology of important ecological traits, namely, skeletal density and thallus thickness near the growing edge, was evaluated in Pseudolithophyllum muricatum (Foslie) Steneck & R.T.

4, 5 Notably, even in spite of the continuous

presence of

4, 5 Notably, even in spite of the continuous

presence of growth inducers, the liver of non–genetically modified rodents never exceeds doubling of its mass, indicating that a precise regulation of tissue size must exist to prevent its further growth, likely incompatible with the survival of the organism. LY2109761 Many xenobiotics able to induce liver enlargement are ligands of nuclear receptors of the steroid/thyroid receptor superfamily6 and, interestingly, are also liver nongenotoxic carcinogens.7–9 In spite of several studies, the key molecular events that govern the tumoral potency of ligands of nuclear receptors are still unclear. The breakthrough that many compounds with liver tumor–promoting ability are also potent inducers of hepatocyte proliferation led to the hypothesis that the mechanisms by which these Imatinib in vivo agents cause liver neoplasia are a consequence of their mitogenic capacity that ultimately results in an increased rate of mutation.10 However, this hypothesis has been questioned by the findings that the proliferative response of the liver to these mitogens is lost very shortly,11, 12 suggesting that the hyperplastic liver becomes refractory to further mitogenic stimuli. These findings

also suggest that the tumors arising in these enlarged livers may be the consequence of the escape of genetically damaged cells from the regulatory Exoribonuclease mechanisms governing the size of the organ. Thus, the identification of the molecular mechanisms responsible for the refractoriness of the enlarged liver to further mitogenic stimuli is critical for improving our knowledge of the control of organ size, and also for determining whether dysregulation of these pathways is a possible mechanism

for the clonal expansion of resistant hepatocytes and their progression to hepatocellular carcinoma (HCC). Recent studies in both Drosophila and mammals have implicated the Hippo signaling pathway as a potent regulator of organ size and tissue homeostasis.13, 14 The mammalian Hippo cascade inactivates its primary effector Yes-associated protein (YAP) by promoting its cytoplasmic localization in an S127 phosphorylation-dependent manner, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased activity of YAP, which binds to transcription factors and regulates transcription of target genes involved in cell growth, proliferation, and survival. Using a conditional YAP transgenic mouse model, it was shown that overexpression of YAP in mice leads to HCC development, suggesting a direct link between dysregulation of the Hippo size-control pathway and liver tumorigenesis.

This study was approved by the institutional review board of Yama

This study was approved by the institutional review board of Yamaguchi University Hospital (H25-8). Venous blood samples were obtained in the morning after overnight fasting. Complete blood cell counts; prothrombin time (PT); and serum levels of total bilirubin,

aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase, total protein, albumin, total cholesterol, triglycerides, fasting glucose and immunoreactive insulin were measured in all patients by standard laboratory techniques. Hemoglobin A1c levels were measured in 60 patients. In addition, we calculated FIB-4, a simple and non-invasive index of fibrosis.[18] selleck The index was calculated automatically using the following formula: age (years) × AST (IU/L) / platelet count (109/L) × ALT (IU/L)1/2. For cut-off values, we used previously designated values: FIB-4 index of less than 1.45 and more than 3.25.[18, 19] The ratio of BCAA to tyrosine level and serum levels of BCAA and tyrosine were assayed using a commercially available kit (Daiyacolor-BTR, Toyobo, Osaka, Japan), in which the normal ranges of BTR, BCAA and tyrosine in healthy subjects were 4.41–10.05, 344–713 and 51–98 μmol/L, respectively. Insulin resistance was evaluated on the basis of fasting levels of plasma glucose and insulin, according

to HOMA-IR.[20] HOMA-IR was calculated using the following formula: glucose (mg/dL) × insulin (μU/mL) / 405. The presence of IR was defined as a HOMA-IR of 2.5 or more; this HOMA-IR Galunisertib mw value has previously been used as a cut-off

indicating a high Selleck Cetuximab probability of IR.[18] Histological examination was performed in 31 patients (echo-guided liver biopsy in 27 patients and surgical resection in four patients); 40 patients did not undergo histological examination. Echo-guided liver biopsy was performed using a 16-G biopsy needle. Fibrosis was staged according to the METAVIR score as follows: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis.[21] The data are expressed as mean ± standard deviation. The correlation between HOMA-IR and each variable was evaluated by Spearman’s rank correlation coefficient. A receiver–operator curve (ROC) was generated by plotting the sensitivity against 1-specificity. The area under the curve (AUC) was calculated to compare the predictive validity of variables and to determine optimal cut-off values to predict a high HOMA-IR (≥2.5), as follows: AUC of more than 0.9, high accuracy; 0.7–0.9, moderate accuracy; 0.5–0.7, low accuracy; and 0.5, a chance result.[22, 23] An AUC of 0.7 or more reflected the discriminative power to predict HOMA-IR outcome within the observed range of each variable. Univariate and multivariate analyses were performed using logistic regression.

This study was approved by the institutional review board of Yama

This study was approved by the institutional review board of Yamaguchi University Hospital (H25-8). Venous blood samples were obtained in the morning after overnight fasting. Complete blood cell counts; prothrombin time (PT); and serum levels of total bilirubin,

aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase, total protein, albumin, total cholesterol, triglycerides, fasting glucose and immunoreactive insulin were measured in all patients by standard laboratory techniques. Hemoglobin A1c levels were measured in 60 patients. In addition, we calculated FIB-4, a simple and non-invasive index of fibrosis.[18] selleck The index was calculated automatically using the following formula: age (years) × AST (IU/L) / platelet count (109/L) × ALT (IU/L)1/2. For cut-off values, we used previously designated values: FIB-4 index of less than 1.45 and more than 3.25.[18, 19] The ratio of BCAA to tyrosine level and serum levels of BCAA and tyrosine were assayed using a commercially available kit (Daiyacolor-BTR, Toyobo, Osaka, Japan), in which the normal ranges of BTR, BCAA and tyrosine in healthy subjects were 4.41–10.05, 344–713 and 51–98 μmol/L, respectively. Insulin resistance was evaluated on the basis of fasting levels of plasma glucose and insulin, according

to HOMA-IR.[20] HOMA-IR was calculated using the following formula: glucose (mg/dL) × insulin (μU/mL) / 405. The presence of IR was defined as a HOMA-IR of 2.5 or more; this HOMA-IR Peptide 17 ic50 value has previously been used as a cut-off

indicating a high others probability of IR.[18] Histological examination was performed in 31 patients (echo-guided liver biopsy in 27 patients and surgical resection in four patients); 40 patients did not undergo histological examination. Echo-guided liver biopsy was performed using a 16-G biopsy needle. Fibrosis was staged according to the METAVIR score as follows: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis.[21] The data are expressed as mean ± standard deviation. The correlation between HOMA-IR and each variable was evaluated by Spearman’s rank correlation coefficient. A receiver–operator curve (ROC) was generated by plotting the sensitivity against 1-specificity. The area under the curve (AUC) was calculated to compare the predictive validity of variables and to determine optimal cut-off values to predict a high HOMA-IR (≥2.5), as follows: AUC of more than 0.9, high accuracy; 0.7–0.9, moderate accuracy; 0.5–0.7, low accuracy; and 0.5, a chance result.[22, 23] An AUC of 0.7 or more reflected the discriminative power to predict HOMA-IR outcome within the observed range of each variable. Univariate and multivariate analyses were performed using logistic regression.

Our findings provide a comprehensive overview of hypoxia-induced

Our findings provide a comprehensive overview of hypoxia-induced adaptive mechanisms in humans and could have implications for the treatment of hypoxia-related

acute and chronic disorders in the future. This study represents the analysis of adaptive enterohepatic regulation of intestinal iron absorption under hypoxic conditions and is part of a cooperative project (principal investigators: M. Maggiorini and Th. Lutz) supported by the Zurich Centre for Integrative Human Physiology (ZIHP). Additional Supporting Information may be found in the online version of this article. “
“An increase in circulating concentrations of gastrin or gastrin precursors such as progastrin and glycine-extended gastrin has been proposed to promote the development of colorectal carcinomas (CRC). The aim of this study was to investigate

whether or not circulating gastrin concentrations were increased in patients with an increased Doxorubicin mouse risk of developing CRC. Patients were divided according to their risk into the five following groups: familial adenomatous polyposis (n = 20), hereditary non-polyposis colorectal cancer (n = 53), cluster of common colorectal cancers (n = 13), personal history and/or family history of adenomatous polyps or CRC (n = 150) and controls Opaganib research buy (n = 42). Radioimmunoassay with four region-specific gastrin antisera was used to measure progastrin, glycine-extended gastrin (gastrin-gly), amidated gastrin (gastrin-amide), and total gastrin in peripheral blood taken at the time of colonoscopy. Compared with the control group, familial adenomatous polyposis patients had significantly higher median values of total gastrin (29.8 pM vs 16.9 pM, P = 0.003) and gastrin-amide (17.1 pM vs 12.0 pM, P = 0.015). Patients with a personal or family

history of adenomatous polyps or CRC also had higher circulating concentrations of total gastrin (21.8 pM) compared with controls (P < 0.05), while patients from all groups who presented with an adenomatous polyp on the day of colonoscopy had higher concentrations of total ROS1 gastrin, progastrin, and gastrin-amide than patients without polyps. Concentrations of gastrin precursors are increased in particular groups with an increased risk of developing CRC. “
“Met, the transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF), is known to function as a potent antiapoptotic mediator in normal and neoplastic cells. Herein we report that the intracellular cytoplasmic tail of Met has evolved to harbor a tandem pair of caspase-3 cleavage sites, which bait, trap, and disable the active site of caspase-3, thereby blocking the execution of apoptosis. We call this caspase-3 cleavage motif the Death Defying Domain (DDD). This site consists of the following sequence: DNAD-DEVD-T (where the hyphens denote caspase cleavage sites).