The mean Quan-Charlson comor-bidity index for patients in the first, second, third, and fourth quartiles of healthcare

costs were 0.3, 0.5, 0.5, and 0.8, respectively. Greater than 90 %of patients in each quartile were non-cirrhotic. The corresponding proportion of patients with cirrhosis at baseline was 0.9%, 1.6%, 1.5%, and 2.5 %and end stage liver disease (ESLD) at baseline was 0.9%, 1.6%, 2.8 selleck inhibitor %and 6.3%, respectively. Compared to the lowest costs quartile group, the highest quartile group had a higher proportion of patients with diabetes (17.2 %vs. 6.1%), psychiatric disease (11.8 %vs. 5.3%), depression (11.9 %vs. 2.8%), substance abuse (6.9 %vs. 3.0%), ≥2 CHC-related conditions (16.4 %vs. 3.2%), and ≥2 non-CHC conditions (4.9 %vs. 1.6%). The strongest predictors of being in the highest cost quartile were ESLD (odds ratio relative to first quartile [OR; 95%CI]; 3.00 [1.45-6.21]), having two or more non-CHC conditions find more (OR: 1.92 [1.25-2.96]), and medical visits to a gastroenterologist (OR: 1.32 [1.05-1.66]). Conclusions: This real-world study suggests that CHC patients with the highest healthcare resource utilization and costs had a high level

of comorbidity at baseline, and that non-CHC conditions are strong predictors of high healthcare costs. Since the majority of patients across quartiles of HRU were non-cirrhotic, liver disease severity alone does not fully predict high HRU consumption, although when present it is a predictor of high HRU. Disclosures: Joyce LaMori – Employment: Janssen Scientific Affairs, LLC; Stock Shareholder: Johnson & Johnson Neeta Tandon – Employment: Johnson & Johnson Co Francois Laliberte – Grant/Research Support: Janssen Scientific Affairs 上海皓元医药股份有限公司 Guillaume

Germain – Grant/Research Support: Janssen Scientific Affairs, LLC D. Pilon – Employment: Analysis Group Patrick Lefebvre – Grant/Research Support: Janssen Scientific Affairs Avinash Prabhakar – Employment: Janssen Scientific Affairs, LLC Background: More than 200,000 individuals are estimated to have chronic HCV infection in Poland; however, only 15 %have been diagnosed. A modeling approach was used to examine HCV-related disease progression and evaluate the strategies required to control disease burden or eliminate HCV disease. Methods: The infected population and associated disease progression were modeled using 36 age- and gender-defined cohorts to track HCV incidence, prevalence, hepatic complications and mortality. Baseline assumptions and transition probabilities were extracted from the literature. The impacts of two scenarios on HCV-related disease burden were considered through increases in SVR, treatment and diagnosis (elimination only). Results: Under the baseline scenario, 201,000 individuals were chronically infected in Poland in 2013. In 2013, it is estimated that 76 %of the infected population was born between 1949 and 1988.

The mean Quan-Charlson comor-bidity index for patients in the first, second, third, and fourth quartiles of healthcare

costs were 0.3, 0.5, 0.5, and 0.8, respectively. Greater than 90 %of patients in each quartile were non-cirrhotic. The corresponding proportion of patients with cirrhosis at baseline was 0.9%, 1.6%, 1.5%, and 2.5 %and end stage liver disease (ESLD) at baseline was 0.9%, 1.6%, 2.8 Selleckchem KU-57788 %and 6.3%, respectively. Compared to the lowest costs quartile group, the highest quartile group had a higher proportion of patients with diabetes (17.2 %vs. 6.1%), psychiatric disease (11.8 %vs. 5.3%), depression (11.9 %vs. 2.8%), substance abuse (6.9 %vs. 3.0%), ≥2 CHC-related conditions (16.4 %vs. 3.2%), and ≥2 non-CHC conditions (4.9 %vs. 1.6%). The strongest predictors of being in the highest cost quartile were ESLD (odds ratio relative to first quartile [OR; 95%CI]; 3.00 [1.45-6.21]), having two or more non-CHC conditions LY294002 manufacturer (OR: 1.92 [1.25-2.96]), and medical visits to a gastroenterologist (OR: 1.32 [1.05-1.66]). Conclusions: This real-world study suggests that CHC patients with the highest healthcare resource utilization and costs had a high level

of comorbidity at baseline, and that non-CHC conditions are strong predictors of high healthcare costs. Since the majority of patients across quartiles of HRU were non-cirrhotic, liver disease severity alone does not fully predict high HRU consumption, although when present it is a predictor of high HRU. Disclosures: Joyce LaMori – Employment: Janssen Scientific Affairs, LLC; Stock Shareholder: Johnson & Johnson Neeta Tandon – Employment: Johnson & Johnson Co Francois Laliberte – Grant/Research Support: Janssen Scientific Affairs MCE公司 Guillaume

Germain – Grant/Research Support: Janssen Scientific Affairs, LLC D. Pilon – Employment: Analysis Group Patrick Lefebvre – Grant/Research Support: Janssen Scientific Affairs Avinash Prabhakar – Employment: Janssen Scientific Affairs, LLC Background: More than 200,000 individuals are estimated to have chronic HCV infection in Poland; however, only 15 %have been diagnosed. A modeling approach was used to examine HCV-related disease progression and evaluate the strategies required to control disease burden or eliminate HCV disease. Methods: The infected population and associated disease progression were modeled using 36 age- and gender-defined cohorts to track HCV incidence, prevalence, hepatic complications and mortality. Baseline assumptions and transition probabilities were extracted from the literature. The impacts of two scenarios on HCV-related disease burden were considered through increases in SVR, treatment and diagnosis (elimination only). Results: Under the baseline scenario, 201,000 individuals were chronically infected in Poland in 2013. In 2013, it is estimated that 76 %of the infected population was born between 1949 and 1988.

Conclusion: 1. Heartburn is a common symptom in the digestive system, this symptom can be found in a variety of diseases, Common species of diseases can be divided into RE, NERD and FH,NERD and FH is heterogeneous diseases with different characteristics.2. Combined with esophageal pH monitoring, symptom index and PPI trial, NERD

subdivided into 3 subgroups: excessive acid exposure, normal acid exposure and positive SI, normal pH monitoring and negative SI but positive PPI trial, There were significant differences of the degree of esophageal acid exposure among 3 subgroups of NERD3. The degree of esophageal acid exposure of NERD group(pH+ or pH−) of significantly was higher than that of the FH group. Key selleckchem Word(s): 1. functional heartburn; 2. pH monitoring; 3. GERD; Presenting Author: QIAONI PANG Additional Authors: XIN WANG Corresponding Author: QIAONI PANG Affiliations: Xi-jing Hospital of Digestive Disease the

Fourth Military Medical University Objective: The clinical pathway (CP) was a treatment management with strict working sequence and precise time request for the monitoring, curing, recovering and nursing of a specific disease during a well-defined period of time. The clinical nursing pathway (CNP) is Belinostat chemical structure one of the most important departments of CP. The CNP included some series protocol program execution and feedback, and different from the curing. The option of the pathway was dependent on the CP implemented by the doctor inalienably. Currently, there’s a misunderstanding

that the CNP is absolutely independent of the clinical treatments, which can be explained that the CNP doesn’t combine with CP closely. Methods: In the present study, we developed a new method of CNP about nursing work, which was referred to the internal and international advanced experiments and adopted the ideology 上海皓元 of systematic standardization template. Based on “The Clinical Pathway of Adjuvant Chemotherapy for Gastric Cancer (ACGC)” (Version 2012), we divided the nursing works into four sections including education, assessment, observation and treatment for all four stages, and then each section was further divided into three procedures including universal, alternative and variation procedures. The new CNP strategy is composed of these procedures according to combination and optimization.

Maintaining a weight loss of 5–10% significantly improves histological severity,[54] but frequently occurring subsequent weight gain leads to the recurrence of NASH.[55] Even moderate physical exercise, such as treadmill walking, improves

markers of apoptosis and insulin sensitivity in NAFLD.[56] The dietary composition is also of great importance. A 2% increment in energy intake from trans fats resulted in a 0.77-cm waist gain over 9 years,[57] and reduction of harmful trans fats improved histological features in a mouse model despite persistent obesity.[29] Even if all these measure are effective, (adjunctive) pharmacological therapies will still be required for the majority of patients with NASH. The severity of NASH and the risk of progression correlate with hepatocyte injury that often includes necroapoptosis, and the associated inflammation. Necroapoptosis involves cell death signaling pathways, which lead to Bortezomib nmr the activation of caspases, cellular proteases that degrade structural proteins required for the cell survival.[58] Inhibition of caspases has been proposed as a therapeutic approach in inflammation-associated disease.[59] In mice on a methionine-choline-deficient (MCD) diet, a model of steatohepatitis that lacks features of the metabolic syndrome but displays features of hepatocyte lipoapoptosis characteristic

of NASH, hepatocyte-specific deletion of caspase 8 ameliorated hepatic inflammation, oxidative stress, and liver injury.[60] In mice with a mutation Palbociclib in vitro of the leptin receptor (db/db) and on the MCD diet, hepatocyte apoptosis and inflammation were suppressed by the pan-caspase inhibitor VX-166.[61] In a double-blind, randomized phase II study of 124 patients with NASH, GS-9450, an inhibitor of caspases 1, 8, and 9, reduced serum

ALT and cytokeratin-18 fragments at 4 weeks of treatment.[62] However, the compound was later withdrawn due to safety concerns in patients with chronic hepatitis C (http://www.gilead.com/pr_1414682). However, dampening necroapoptosis in active NASH remains an attractive target to reduce the amount of cell death and subsequent fibrosis, and prevent disease progression. On the other hand, increasing cellular viability during inflammation also raises concerns MCE公司 of malignancy, and antiapoptotic agents likely need to be given in a small therapeutic window. Adenosine is a physiological modulator of tissue responses to injury, and regulates cell survival, immuno-inflammatory reactions, and tissue repair involving four adenosine receptors (A1, A2A, A2B, and A3) in an auto and paracrine fashion.[63] In rats that are on the MCD diet, activation of the adenosine A2A receptor, which is expressed on inflammatory cells and hepatic stellate cells (HSCs), with the agonist CGS21680 reduced inflammatory cell activation, the subsequent JNK cascade in hepatocytes, and fibrosis, without affecting steatosis.

Maintaining a weight loss of 5–10% significantly improves histological severity,[54] but frequently occurring subsequent weight gain leads to the recurrence of NASH.[55] Even moderate physical exercise, such as treadmill walking, improves

markers of apoptosis and insulin sensitivity in NAFLD.[56] The dietary composition is also of great importance. A 2% increment in energy intake from trans fats resulted in a 0.77-cm waist gain over 9 years,[57] and reduction of harmful trans fats improved histological features in a mouse model despite persistent obesity.[29] Even if all these measure are effective, (adjunctive) pharmacological therapies will still be required for the majority of patients with NASH. The severity of NASH and the risk of progression correlate with hepatocyte injury that often includes necroapoptosis, and the associated inflammation. Necroapoptosis involves cell death signaling pathways, which lead to learn more the activation of caspases, cellular proteases that degrade structural proteins required for the cell survival.[58] Inhibition of caspases has been proposed as a therapeutic approach in inflammation-associated disease.[59] In mice on a methionine-choline-deficient (MCD) diet, a model of steatohepatitis that lacks features of the metabolic syndrome but displays features of hepatocyte lipoapoptosis characteristic

of NASH, hepatocyte-specific deletion of caspase 8 ameliorated hepatic inflammation, oxidative stress, and liver injury.[60] In mice with a mutation Fulvestrant of the leptin receptor (db/db) and on the MCD diet, hepatocyte apoptosis and inflammation were suppressed by the pan-caspase inhibitor VX-166.[61] In a double-blind, randomized phase II study of 124 patients with NASH, GS-9450, an inhibitor of caspases 1, 8, and 9, reduced serum

ALT and cytokeratin-18 fragments at 4 weeks of treatment.[62] However, the compound was later withdrawn due to safety concerns in patients with chronic hepatitis C (http://www.gilead.com/pr_1414682). However, dampening necroapoptosis in active NASH remains an attractive target to reduce the amount of cell death and subsequent fibrosis, and prevent disease progression. On the other hand, increasing cellular viability during inflammation also raises concerns 上海皓元医药股份有限公司 of malignancy, and antiapoptotic agents likely need to be given in a small therapeutic window. Adenosine is a physiological modulator of tissue responses to injury, and regulates cell survival, immuno-inflammatory reactions, and tissue repair involving four adenosine receptors (A1, A2A, A2B, and A3) in an auto and paracrine fashion.[63] In rats that are on the MCD diet, activation of the adenosine A2A receptor, which is expressed on inflammatory cells and hepatic stellate cells (HSCs), with the agonist CGS21680 reduced inflammatory cell activation, the subsequent JNK cascade in hepatocytes, and fibrosis, without affecting steatosis.

We sought to determine the relation of sex hormones with histologic pattern and severity in pediatric NAFLD. Methods: 73 children (<18 y) with biopsied NAFLD were evaluated in a cross-sectional prospective studyfrom the NASH CRN. Clinical data, sex hormone levels, and histologic features were compared between sexes. Hormones

were assayed using ELISA (androstenedione, DHEA-S, estradiol, estrone, leptin, SHBG, testosterone and adiponectin). Scored histology features included steatosis, inflammation and fibrosis as well as NAFLD patterns assessed by NASH CRN pathologists. Odds ratios and 95% CI’s were calculated between each sex hormone and histologic feature adjusted for sex, ethnicity and Tanner stage. Independent MK-2206 in vivo predictors of NASH diagnosis were determined from a stepwise multinomial logistic regression. Results: Subjects were 12.9 ± 2.6 yrs, 68% male, 52.1% Hispanic, average

BMI Z-score 2.3 ± 0.4 and Tanner stage 2.6 ±1.5. Overall, 37% had “NAFLD, No NASH, ” 14% GS-1101 solubility dmso had Zone 3 NASH, 22% had Zone 1 NASH and 27% had “Definite NASH”.32% had mild, 27% had moderate and 41% had severe steatosis. Sex hormones influenced NAFLD histology and patterning. Estradiol and estrone were significantly decreased in Zone 1 NASH vs. “NAFLD, No NASH” (Estradiol= 52.9土 15.5 vs.73.3土 30.8pg/mL, OR=0.62, p=0.01; Estrone= 40.38± 13.3 vs.61.9± 27.6 pg/mL, OR=0.58, p=0.007). Estrogen precursors were higher in mild steatosis as compared to moderate/severe (Estradiol= 66.3± 23.9 vs.64.5± 22.7pg/mL, OR=1.28, p=0.11; Estrone= 54.1± 24.9 vs.50.8± 23.7pg/mL, OR=1.24, MCE公司 p=0.14). Androstene-dione was decreased significantly in Zone 1 NASH vs. “NAFLD, No NASH” (1.01± 0.8 vs.1.2± 0.9ng/mL, OR=0.28, p=0.03). Adiponectin was significantly decreased in subjects with Definite NASH vs. “NAFLD, No NASH” (6467土 2834 vs.8676土 4461ng/mL; OR=0.80, p=0.04). Adiponectin and SHBG were decreased in moderate/severe vs. mild steatosis (8049±3354 vs.9862± 4630ng/mL, OR=0.85, p=0.02; 18.9± 9.4 vs.35, 4±

50.1nmol/L, OR 0.91, p = 0.004). Independent predictors of NASH diagnosis were gender, Tanner stage, DHEA-S, estrone, AST and GGT. Conclusions: Sex hormones associate with various aspects of NAFLD histology and patterning and may explain gender differences in NAFLD prevalence, histologic pattern and severity. We speculate these hormones signal through trans-activating mediators of lipid metabolism and inflammation. These clinically significant results warrant validation in larger cohorts. Disclosures: Joel E. Lavine – Consulting: Merck, Crosscare; Grant/Research Support: Janssen Cynthia A. Behling – Grant/Research Support: NASH CRN The following people have nothing to disclose: Elana B. Mitchel, Kathleen Viveiros, Katherine P. Yates, Janis Durelle, Jeffrey B. Schwimmer, Aynur Unalp Arida Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is recognized as an important health concern.

We sought to determine the relation of sex hormones with histologic pattern and severity in pediatric NAFLD. Methods: 73 children (<18 y) with biopsied NAFLD were evaluated in a cross-sectional prospective studyfrom the NASH CRN. Clinical data, sex hormone levels, and histologic features were compared between sexes. Hormones

were assayed using ELISA (androstenedione, DHEA-S, estradiol, estrone, leptin, SHBG, testosterone and adiponectin). Scored histology features included steatosis, inflammation and fibrosis as well as NAFLD patterns assessed by NASH CRN pathologists. Odds ratios and 95% CI’s were calculated between each sex hormone and histologic feature adjusted for sex, ethnicity and Tanner stage. Independent Epigenetics inhibitor predictors of NASH diagnosis were determined from a stepwise multinomial logistic regression. Results: Subjects were 12.9 ± 2.6 yrs, 68% male, 52.1% Hispanic, average

BMI Z-score 2.3 ± 0.4 and Tanner stage 2.6 ±1.5. Overall, 37% had “NAFLD, No NASH, ” 14% CDK inhibitor review had Zone 3 NASH, 22% had Zone 1 NASH and 27% had “Definite NASH”.32% had mild, 27% had moderate and 41% had severe steatosis. Sex hormones influenced NAFLD histology and patterning. Estradiol and estrone were significantly decreased in Zone 1 NASH vs. “NAFLD, No NASH” (Estradiol= 52.9土 15.5 vs.73.3土 30.8pg/mL, OR=0.62, p=0.01; Estrone= 40.38± 13.3 vs.61.9± 27.6 pg/mL, OR=0.58, p=0.007). Estrogen precursors were higher in mild steatosis as compared to moderate/severe (Estradiol= 66.3± 23.9 vs.64.5± 22.7pg/mL, OR=1.28, p=0.11; Estrone= 54.1± 24.9 vs.50.8± 23.7pg/mL, OR=1.24, 上海皓元 p=0.14). Androstene-dione was decreased significantly in Zone 1 NASH vs. “NAFLD, No NASH” (1.01± 0.8 vs.1.2± 0.9ng/mL, OR=0.28, p=0.03). Adiponectin was significantly decreased in subjects with Definite NASH vs. “NAFLD, No NASH” (6467土 2834 vs.8676土 4461ng/mL; OR=0.80, p=0.04). Adiponectin and SHBG were decreased in moderate/severe vs. mild steatosis (8049±3354 vs.9862± 4630ng/mL, OR=0.85, p=0.02; 18.9± 9.4 vs.35, 4±

50.1nmol/L, OR 0.91, p = 0.004). Independent predictors of NASH diagnosis were gender, Tanner stage, DHEA-S, estrone, AST and GGT. Conclusions: Sex hormones associate with various aspects of NAFLD histology and patterning and may explain gender differences in NAFLD prevalence, histologic pattern and severity. We speculate these hormones signal through trans-activating mediators of lipid metabolism and inflammation. These clinically significant results warrant validation in larger cohorts. Disclosures: Joel E. Lavine – Consulting: Merck, Crosscare; Grant/Research Support: Janssen Cynthia A. Behling – Grant/Research Support: NASH CRN The following people have nothing to disclose: Elana B. Mitchel, Kathleen Viveiros, Katherine P. Yates, Janis Durelle, Jeffrey B. Schwimmer, Aynur Unalp Arida Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is recognized as an important health concern.

This is an important practical consideration as we attempt to improve the quality of studies in HCC and minimize risk. None of the studies mandated that an upper endoscopy be performed in order to screen for the presence of varices,

although two studies did introduce this after the occurrence of a serious hemorrhage. The risk of variceal hemorrhage in Ulixertinib patients with cirrhosis is difficult to quantify but has been reported to be as high as 40%.11 In the context of HCC the short- to medium-term risk is particularly important to assess given that in the SHARP study the median duration of sorafenib treatment was 5.3 months and the median overall survival for these patients was 10.7 months. The presence of even small varices is a marker of increased bleeding risk as shown by one prospective Kinase Inhibitor Library in vitro study where (12) the 2-year risk of bleeding was found to be significantly higher in patients with small varices at enrollment compared to those who did not have any varices (12% versus 2%). Several factors have been employed to predict

the risk of variceal hemorrhage, including the size and location of varices (gastric fundus varices of higher risk13), their physical appearance, and variceal pressure as measured by endoscopic gauge.14 The North Italian Endoscopic Club (NIEC) study established a prognostic index—depending on size, presence

of red wale marks, and Child class—which quantified 1-year bleeding risk, a relevant timepoint for a patient with a diagnosis of advanced HCC.15 According to that study there are “high risk” small varices (those that occur in Child C patients or have red wale marks) that may have the same risk of bleeding than a Child A patient 上海皓元医药股份有限公司 with large varices (and prophylaxis is recommended in these patients). Limiting eligibility in HCC studies to Childs A patients—as recommended by the American Association for the Study of Liver Diseases (AASLD)16—would mitigate some of this risk, but—also consistent with current AASLD guidelines17—Child A patients should undergo screening endoscopy unless they have had one in the last 2-3 years (with no varices demonstrated) or last 1-2 years (if small varices had been identified. Five of the studies we reviewed—including both the SHARP and AP studies—were confined to patients with Childs-Pugh grade A cirrhosis. Perhaps the most specific indicator of risk for variceal bleeding is the prior occurrence of a hemorrhagic event with the risk of a subsequent bleeding episode estimated to be 17%-40%,18 but also, in older analyses, as high as 70%.19 Seven of the studies in our analysis excluded patients with a history of active bleeding, although the duration of this was variable, ranging from 30 days to 1 year.

This is an important practical consideration as we attempt to improve the quality of studies in HCC and minimize risk. None of the studies mandated that an upper endoscopy be performed in order to screen for the presence of varices,

although two studies did introduce this after the occurrence of a serious hemorrhage. The risk of variceal hemorrhage in Inhibitor Library cost patients with cirrhosis is difficult to quantify but has been reported to be as high as 40%.11 In the context of HCC the short- to medium-term risk is particularly important to assess given that in the SHARP study the median duration of sorafenib treatment was 5.3 months and the median overall survival for these patients was 10.7 months. The presence of even small varices is a marker of increased bleeding risk as shown by one prospective Galunisertib study where (12) the 2-year risk of bleeding was found to be significantly higher in patients with small varices at enrollment compared to those who did not have any varices (12% versus 2%). Several factors have been employed to predict

the risk of variceal hemorrhage, including the size and location of varices (gastric fundus varices of higher risk13), their physical appearance, and variceal pressure as measured by endoscopic gauge.14 The North Italian Endoscopic Club (NIEC) study established a prognostic index—depending on size, presence

of red wale marks, and Child class—which quantified 1-year bleeding risk, a relevant timepoint for a patient with a diagnosis of advanced HCC.15 According to that study there are “high risk” small varices (those that occur in Child C patients or have red wale marks) that may have the same risk of bleeding than a Child A patient medchemexpress with large varices (and prophylaxis is recommended in these patients). Limiting eligibility in HCC studies to Childs A patients—as recommended by the American Association for the Study of Liver Diseases (AASLD)16—would mitigate some of this risk, but—also consistent with current AASLD guidelines17—Child A patients should undergo screening endoscopy unless they have had one in the last 2-3 years (with no varices demonstrated) or last 1-2 years (if small varices had been identified. Five of the studies we reviewed—including both the SHARP and AP studies—were confined to patients with Childs-Pugh grade A cirrhosis. Perhaps the most specific indicator of risk for variceal bleeding is the prior occurrence of a hemorrhagic event with the risk of a subsequent bleeding episode estimated to be 17%-40%,18 but also, in older analyses, as high as 70%.19 Seven of the studies in our analysis excluded patients with a history of active bleeding, although the duration of this was variable, ranging from 30 days to 1 year.

Specifically, we found that approximately 20% of black American H 89 mouse HA patients carrying the H1 or H2 variation of F8, who therefore received matched (or least-mismatched) infusions with FVIII, developed inhibitors [13]; this is equivalent to the overall rate observed

in prior studies that were likely comprised of relatively few HA patients with black African heritage [31]. On the other hand, black HA patients with the H3 or H4 haplotype, which are mismatched with all currently available recombinant FVIII products, and likely with most of the FVIII contained in plasma-derived FVIII products in the US (which are typically derived from a predominantly white blood donor population), developed inhibitors at about three times the rate of black patients with the H1 or H2 haplotype [13]. As described above, differences between the infused and endogenous FVIII in patients may arise naturally, due to ns-SNPs and/or the causal F8 mutation, or from structural alterations of recombinant products, e.g. due to distinct post-translational modifications, or to sequence engineering for increasing protein expression [30] or prolonging protein half-life in patients’ circulation [32–34]. Thus, patients infused with ‘mismatched’ FVIII may be exposed to neo-epitopes

that can cause immune responses. HA patients with major INK 128 cell line MCE公司 F8 gene deletions or premature stop codons will obviously have the greatest degree of mismatch between their endogenous FVIII and a therapeutic FVIII product. The most common defect causing HA is the intron-22 inversion (I22-inv) that occurs in approximately 40% of all severely affected patients [35]. An intron-22 inverted F8 allele cannot be transcribed into a full-length mRNA as the promoter region and the adjacent gene region containing exons 1–22 have been inverted [36]. In I22-inv patients, exons 1 through 22 are transcribed as a polyadenylated fusion transcript in which two (or more) unrelated 3′-exons have replaced F8 exons

23 through 26. However, intron 22 of the F8 locus also contains two nested genes, F8A and F8B, which are controlled by a CpG-island containing a bidirectional promoter [37,38]. In I22-inv patients, transcription and translation of the F8B gene would be predicted to generate a polypeptide encoded almost entirely by exons 23–26; this putative protein is referred to as FVIIIB. If a partial FVIII protein encoded by the mRNA containing exons 1–22 is expressed, along with the FVIIIB protein, then one would expect that I22-inv patients would be more likely to tolerate infused FVIII, unless ‘mismatched’ amino acid sequences, e.g. at the wild-type exon-22/-23 junction region, were recognized as foreign by their immune systems.